Calcium.

From the (mainly small) intestines, 30%–40% of dietary calcium is absorbed depending on calcium intake and occurs via a saturable transcellular pathway and a nonsaturable, paracellular pathway. Many substances in the gut complex with calcium and reduce its availability for absorption: oxalate, fatty acids, citrate, phosphate, and sulfate.

Oxalate.

Urinary oxalate is derived from endogenous liver production (50%) and dietary sources (50%). About 6%–14% ingested oxalate is absorbed transcellularly and paracellularly, though it varies widely among individuals (10%–70%) and occurs about equally between the small and large intestines. Many substances complex with oxalate, including calcium, magnesium, and oxalate-degrading bacteria (Oxalobacter formigenes) . Coingestion of calcium- and oxalate-containing foods leads to nonabsorbable calcium oxalate complexes and less free oxalate available for absorption. The contribution of O. formigenes to the overall risk of stone formation is not fully understood.

Citrate.

From endogenous and dietary sources, citrate inhibits stone formation by many mechanisms.

• 1.
  

  Complexes with calcium, reducing urinary saturation of calcium salts

  
  
• 2.
  

  Directly prevents spontaneous nucleation of calcium oxalate crystals

  
  
• 3.
  

  Inhibits agglomeration and sedimentation of calcium oxalate crystals

  
  
• 4.
  

  Inhibits the growth of calcium oxalate and calcium phosphate crystals

  
  
• 5.
  

  Enhances the inhibitory effect of Tamm-Horsfall glycoproteins

Magnesium.

Complexes with oxalate; synergistic with citrate; negated by uric acid.

Glycosaminoglycans.

Inhibits calcium oxalate crystal nucleation and aggregation.

Glycoproteins.

Inhibits calcium oxalate nucleation, growth, aggregation, and crystal-urothelial cell binding.

Matrix.

The noncrystalline component of stones (mucoproteins, proteins, carbohydrates, urinary inhibitors), usually 2.5% by weight; can comprise >50% of infectious stones.

Hypercalciuria.

The most common abnormality found in calcium stone formers, occurs in 35%–65% of patients, and defined as >200 mg calcium/day on a calcium and sodium-controlled diet, or >4 mg/kg/day. Dysregulation of calcium metabolism and transport at the intestine, bone, or kidney can lead to hypercalciuria. Historically, hypercalciuria is classified as absorptive (20%–40%), renal (5%–8%) or resorptive (2%–8%; primary hyperparathyroidism) ( Table 27.3 ). Clinically, the distinction between absorptive and renal hypercalciuria is not important because therapy does not change. Elevated serum parathyroid hormone (PTH) warrants evaluation for primary hyperparathyroidism.

Hyperoxaluria.

Defined as urinary oxalate >40 mg/day. Increased urinary oxalate potentiates calcium oxalate stone formation and may trigger renal tubular cell injury, which can promote crystal deposition and growth. Up to half of urinary oxalate is derived from diet (24%–42%), and the rest is from liver metabolism. Causes of hyperoxaluria include primary (urine oxalate >80–100 mg/day, autosomal recessive, faulty glyoxylate metabolism), enteric (intestinal malabsorptive states), dietary (urinary oxalate <80 mg/day, excess dietary oxalate intake), and idiopathic.

Hypocitraturia.

No exact cutoff defines hypocitraturia. Historically, urinary citrate <320 mg/day; more recently <450 mg/day (men) and <550 mg/day (women). An isolated abnormality in 10% and in combination with other abnormalities in 20%–60% of calcium stone formers. Systemic acidosis causes hypocitraturia secondary to enhanced renal tubular reabsorption and decreased synthesis of citrate in peritubular cells. Most hypocitraturia is idiopathic, though it is commonly seen in distal renal tubular acidosis (RTA) (type I), chronic diarrheal states (loss of intestinal bicarbonate/alkali), high animal protein diets, thiazides (hypokalemia and intracellular acidosis), and carbonic anhydrase inhibitors (e.g., topiramate, prevent bicarbonate reabsorption)

Hyperuricosuria.

Defined as urinary uric acid >750 mg/day (women) or >800 mg/day (men) and seen in up to 40% of calcium stone formers. At a urine pH <5.5, undissociated uric acid predominates, while at urine pH >5.5, sodium urate predominates, mainly caused by increased dietary animal protein (purine) intake. Also acquired and hereditary causes (gout, myeloproliferative disorders). Exact mechanism unknown.

Hypercalcemic-induced hypercalciuria

• 1.
  

  Sarcoidosis and granulomatous disease – Sarcoid/granuloma macrophages produce excessive vitamin D ₃ , leading to increased intestinal calcium absorption and bone resorption. High serum and urinary calcium with low serum PTH are suggestive.

  
  
• 2.
  

  Malignancy – Tumors can produce PTH-related protein (PTHrP), which increases intestinal calcium absorption and bone resorption and stimulates vitamin D ₃ synthesis.

  
  
• 3.
  

  Glucocorticoids – promote bone resorption (main effect) and stimulate PTH release.

  
  
• 4.
  

  Vitamin D toxicity

  
  
• 5.
  

  Thyrotoxicosis

Low urine pH.

At low urine pH (<5.5) the undissociated form of uric acid predominates and acts as a nidus for heterogenous nucleation with calcium oxalate. Idiopathic low urine pH was previously called “gouty diathesis.”

Renal tubular acidosis (RTA).

Clinical syndrome of metabolic acidosis caused by impaired renal tubular hydrogen ion secretion (distal or type 1) or bicarbonate reabsorption (proximal or type 2). Three types of RTA: 1, 2, and 4. Type 1 (distal) RTA is the most common and associated with stone formation (≤70% of individuals), usually calcium phosphate, and may be hereditary, acquired, or idiopathic (most common). Classic findings include low serum bicarbonate, hypokalemic, hyperchloremic, nonanion gap metabolic acidosis, bone demineralization, secondary hyperparathyroidism, elevated urine pH (>6.0), hypercalciuria, and profound hypocitraturia. Nephrocalcinosis is common.

Hypomagnesuria.

Seen in up to 11% of stone formers. Magnesium inhibits stone formation by complexing with oxalate and calcium salts.

Uric acid stones.

The three main determinants of uric acid stone formation are low pH (most important), low urine volume, and hyperuricosuria. Most uric acid stone formers have normal urinary uric acid excretion and persistently low urine pH. This differs from hyperuricosuric calcium stone formers with high urinary uric acid and normal pH. Uric acid is a weak acid, pKa 5.35 at 37°C. At low urine pH (<5.5), uric acid predominates and easily precipitates, while at higher urine pH (>6), sodium urate predominates (20 times more soluble than uric acid). Acquired causes of uric acid stones include metabolic syndrome, diabetes mellitus, and high animal protein intake.

Cystine stones.

Cystinuria is autosomal recessive disorder (rarely autosomal dominant with incomplete penetrance) whereby dibasic amino acids cystine ornithine, lysine, and arginine are not reabsorbed from the urine. Cystine, with the lowest solubility, readily precipitates to form stones. Cystine is a dimer composed of two cysteine molecules linked via a disulfide bond. Cystine solubility increases with elevating urinary pH. Classified based on the chromosomal mutation: type A (chromosome 2), type B (chromosome 19), and type AB (both chromosomes). Homozygotes (type AB) excrete much more cystine, have more active stone disease, and present at an earlier age. Type B heterozygotes have significantly higher urinary cystine than type A heterozygotes, though stone formation is similar between the two and is usually infrequent and much less common than in homozygotes.

Infectious stones.

These account for 5%–15% of all stones and are more common in women than men (2:1). Composed primarily of magnesium ammonium phosphate hexahydrate (struvite), carbonate apatite (calcium phosphate), and sometimes ammonium urate. Associated with urinary infection by urease-splitting bacteria, mainly Proteus (most common), Klebsiella, Pseudomonas, and Staphylococcus spp. ( Table 27.4 ). Carbonate apatite precipitates at urine pH >6.8, and struvite precipitate at urine pH >7.2. Rapid stone growth can occur with recurrent or persistent urinary tract infections (UTIs). Urealysis produces alkaline urine and higher concentrations of ammonium, carbonate, and phosphate.

Matrix stones.

Stones of pure matrix are rare, radiolucent, poorly visualized on noncontrast computed tomography (CT), and potentially mistaken for tumor or uric acid stones depending on the imaging study. They are more common in women, and associated with recurrent UTIs ( Proteus spp., E. coli ), alkaline urine, hemodialysis, and CKD (increased proteinuria). Matrix is composed of mucoproteins (two thirds) and mucopolysaccharides (one third). Pure matrix stones may contain >65% protein, while calcium-based stones usually contain ≤3% matrix. Matrix is thought to serve as a nidus for stone growth.

Medication-related stones.

Drug-induced stones form either directly as crystallized drug or its metabolite or indirectly from unfavorable urine changes caused by the drug that promote stone formation ( Table 27.5 ).