Urolithiasis forms when urine becomes supersaturated with stone-forming salts and the balance of promoters and inhibitors tips toward crystallisation. Stone type is driven by specific metabolic derangements, urine pH, and — for struvite — infection, and understanding these underpins both prevention and treatment.
Epidemiology
- Lifetime prevalence is roughly 1–15%, varying by age, sex, race, geography, and BMI.
- Uncommon before age 20; incidence peaks in the 40s–60s.
- More common in men, though the gap is narrowing; highest among White populations and in the southeastern US.
- BMI, waist size, and weight gain correlate positively with stone risk. Asymptomatic renal stones are found in ~10% of screened populations.
Stone Formation and Inhibitors
Urine must be supersaturated for stones to form, but supersaturation alone is insufficient because of urinary inhibitors. The solubility product is the equilibrium point of saturation; above it (the metastable state) crystals grow on pre-existing crystals (heterogeneous nucleation), and only when the formation product is exceeded does spontaneous (homogeneous) nucleation occur. Inhibitors prevent or delay crystallisation in the supersaturated state.
Inhibitors of calcium oxalate/phosphate crystallisation (6): nephrocalcin, magnesium (complexes oxalate), bikunin, citrate (the most important), Tamm-Horsfall mucoprotein (the most abundant urinary protein), and uropontin. No known inhibitors affect uric acid crystallisation. Citrate acts by complexing calcium (lowering calcium oxalate saturation), inhibiting spontaneous precipitation and crystal agglomeration, inhibiting calcium oxalate and (more strongly) calcium phosphate crystal growth, and preventing heterogeneous nucleation of calcium oxalate by monosodium urate.
Stones have a crystalline component (calcium is the most common constituent) and a non-crystalline matrix (≈2.5% of stone weight, ~65% protein). Randall plaques — calcium apatite originating in the basement membrane of the thin loops of Henle — extend to a subepithelial location and anchor calcium oxalate stone formation.
Mineral Metabolism
Calcium — 30–40% of dietary calcium is absorbed (mostly small intestine, ~10% colon), with fractional absorption rising on a low-calcium diet and falling on a high-calcium diet. Oxalate, citrate, phosphate, sulfate, and fatty acids complex calcium and reduce its absorption.
- PTH (secreted in response to low serum calcium): increases renal calcium reabsorption and phosphate excretion (primary effect), stimulates 1α-hydroxylase (converting 25-OH-vitamin D to calcitriol; also stimulated by hypophosphataemia), and increases calcium release from bone.
- Calcitriol [1,25(OH)₂D₃, active vitamin D]: the most potent stimulator of intestinal calcium absorption (PTH does not target the intestine), increases renal calcium and phosphate reabsorption, increases bone calcium release, and inhibits PTH release.
Oxalate — only 6–14% of ingested oxalate is absorbed (throughout the gut). Absorption is reduced by oxalate-degrading bacteria (Oxalobacter formigenes) and oxalate-binding cations (calcium, magnesium). Absorbed oxalate is nearly completely excreted in urine; about half of urinary oxalate is dietary and the rest endogenous (hepatic, from ascorbic acid and glycine).
Classification
| Stone | Frequency |
|---|---|
| Calcium oxalate | 60% |
| Hydroxyapatite | 20% |
| Uric acid | 7% |
| Struvite | 7% |
| Calcium phosphate / brushite | 2% |
| Cystine | 1–3% |
| Triamterene, silica, 2,8-dihydroxyadenine | <1% each |
Metabolic Risk Factors
Hypercalciuria
The most common abnormality in calcium stone formers (and the most common cause of microscopic haematuria in children).
| Type | Serum Ca | PTH | Mechanism |
|---|---|---|---|
| Absorptive | Normal | Normal/suppressed | ↑ intestinal calcium absorption → transient ↑ serum Ca → suppressed PTH → ↑ urinary Ca. Type I: hypercalciuria regardless of diet; type II: only on a normal diet |
| Renal (leak) | Normal | Elevated | Impaired renal calcium reabsorption → urinary loss → secondary hyperparathyroidism; high fasting urinary calcium |
| Resorptive | Elevated | Elevated | Usually primary hyperparathyroidism (adenoma) → bone resorption + ↑ calcitriol, with hypophosphataemia. Recurrent 100% brushite stones should raise suspicion for primary HPT |
| Idiopathic | Normal | Normal | Hypercalciuria without a serum abnormality |
Elevated PTH with high fasting urinary calcium differentiates renal from absorptive hypercalciuria. Rare resorptive causes include malignancy (PTHrP), sarcoidosis (macrophage 1α-hydroxylase), thyrotoxicosis, and vitamin D toxicity.
Hyperoxaluria
Four types: primary (rare autosomal recessive defect of glyoxylate metabolism), enteric, dietary, and idiopathic. In enteric hyperoxaluria (fat malabsorption — IBD, celiac, bowel resection, Roux-en-Y bypass), unabsorbed fatty acids saponify calcium, leaving more free oxalate for absorption, and bile salts increase colonic permeability to oxalate; the result is calcium oxalate stones with hypocitraturia and hypomagnesuria from chronic metabolic acidosis. Manage with calcium supplementation timed with meals (not oxalate restriction alone). Dietary hyperoxaluria comes from oxalate-rich foods (rhubarb, chocolate, pepper, nuts, tea, spinach, beets, berries); keep calcium intake moderate (do not severely restrict) and limit vitamin C to ≤2 g/day (a substrate for oxalate).
Hyperuricosuria
May cause pure uric acid stones or calcium oxalate stones (heterogeneous nucleation by monosodium urate). The most common cause is increased dietary purine intake; others include gout, myelo-/lymphoproliferative disorders, multiple myeloma, thalassaemia, haemolytic disorders, pernicious anaemia, haemoglobinopathies, secondary polycythaemia, HGPRT deficiency (Lesch-Nyhan), PRPP-synthetase overactivity, and hereditary renal hypouricaemia.
Renal Tubular Acidosis
A metabolic acidosis, acquired (mnemonic A CASH POT: Analgesic nephropathy, idiopathic hyperCalciuria, ATN, Sarcoidosis, Hyperparathyroidism, Pyelonephritis, Obstructive uropathy, renal Transplant) or inherited.
| Type | Defect | Stones | Features |
|---|---|---|---|
| 1 (distal) | Impaired H⁺ secretion (α-intercalated cells) | Common (up to 70%); calcium phosphate | Urine pH >6.0, hyperchloraemic non-anion-gap acidosis, hypercalciuria, hypocitraturia, hypokalaemia, nephrocalcinosis |
| 2 (proximal) | Impaired HCO₃⁻ reabsorption | Uncommon | Serum HCO₃⁻ 15–18, urine pH <5.5 at steady state; citrate not low |
| 4 (distal) | Impaired mineralocorticoid response | Uncommon | Chronic renal damage; hyperkalaemia |
Incomplete type 1 RTA is confirmed by inadequate urinary acidification after an ammonium chloride load; potassium citrate corrects the acidosis and hypokalaemia.
Hypomagnesiuria, Hypocitraturia, and Urine pH
- Hypomagnesiuria — rare; most often from IBD malabsorption or chronic thiazide therapy. Low magnesium reduces inhibitory activity and lowers urinary citrate.
- Hypocitraturia — acid-base state is the primary determinant (acidosis lowers citrate, alkalosis raises it). Causes (mnemonic DIRT): chronic Diarrhoea, Idiopathic, type 1 RTA, Thiazides. Severe hypocitraturia should raise suspicion for RTA.
- Urine pH — at low pH (<5.5) undissociated uric acid predominates, promoting uric acid and (via heterogeneous nucleation) calcium oxalate stones. Chronic metabolic acidosis lowers urine pH and citrate while raising calcium.
Stone Types
Calcium
Urinary calcium and oxalate are equal contributors to calcium oxalate stones, driven by the metabolic derangements above (hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia).
Uric Acid
Three determinants: low urine pH (<5.5, most important), low urine volume, and hyperuricosuria. Diabetics form uric acid stones ~6× more often (insulin resistance impairs renal ammoniagenesis → low urine pH; 34% of diabetic vs 6% of non-diabetic stone formers). Other causes: obesity, metabolic syndrome, tumour lysis, volume depletion, high animal protein, chronic diarrhoea, and uricosuric drugs.
Calcium Phosphate
Associated with type 1 RTA, primary hyperparathyroidism, medullary sponge kidney, and carbonic anhydrase inhibitors.
Cystine
From cystinuria — autosomal recessive (SLC7A9 or SLC3A1), impairing renal tubular and intestinal reabsorption of Cystine, Ornithine, Lysine, Arginine (COLA). Poorly radio-opaque; the sodium nitroprusside spot test turns urine purple and is used for screening.
Struvite (Infection)
Magnesium ammonium phosphate stones form only with infection by urease-producing organisms — Proteus (most common), Klebsiella, Pseudomonas, Staphylococcus aureus (most E. coli do not produce urease). Urease hydrolyses urea to ammonium and CO₂, raising urine pH and precipitating struvite. More common in females (2:1) and those prone to recurrent UTI (diabetics, elderly, urinary stasis, neurogenic bladder, spinal-cord injury). Commonly form staghorn calculi (as can cystine, calcium oxalate monohydrate, and uric acid).
Other Stones
- Matrix — rare; ~65% organic protein; associated with urea-splitting UTI, prior stones/surgery, and obstruction; radiolucent and can mimic a soft-tissue mass.
- Xanthine — inherited xanthine dehydrogenase deficiency; high-dose allopurinol can rarely precipitate it; radiolucent.
- 2,8-dihydroxyadenine — adenine phosphoribosyltransferase deficiency (autosomal recessive); radiolucent.
- Ammonium acid urate — laxative abuse, recurrent UTI/uric acid stones, IBD; rare in industrialised nations.
Medication-Associated Stones
Mnemonic Lotta Good Drugs Cause Calculi FIT TEST: laxatives, guaifenesin, vitamin D, vitamin C (→ oxalate), carbonic anhydrase inhibitors (acetazolamide → calcium phosphate), furosemide, thiazides (intracellular acidosis → hypocitraturia), indinavir (HIV protease inhibitor — radiolucent, may not be seen on CT), topiramate (carbonic anhydrase inhibitor → distal-RTA-like picture; treat with potassium citrate or stop), triamterene (radiolucent), ephedrine, silicates, and TMP/SMX.
Anatomic Predisposition
UPJ obstruction, horseshoe kidney, caliceal diverticulum, and medullary sponge kidney (congenital cystic dilatation of collecting tubules → stasis, nephrocalcinosis, and a distal-RTA-like picture; hyperechoic papillae with clustered small stones on imaging). For UPJO and horseshoe kidney an underlying metabolic abnormality is still required for stone formation, and correcting the UPJO does not prevent recurrence in most patients.
Self-Test
1. List the inhibitors of calcium oxalate formation. Nephrocalcin, magnesium, bikunin, citrate, Tamm-Horsfall protein, and uropontin.
2. What are the functions of PTH? Stimulates renal calcium reabsorption and phosphate excretion, stimulates calcium release from bone, and stimulates 1α-hydroxylase to produce active vitamin D.
3. What are the functions of vitamin D? Increases intestinal calcium absorption (PTH does not target the intestine), increases renal calcium and phosphate reabsorption (PTH increases phosphate excretion), increases bone calcium release, and inhibits PTH release.
4. What is the most common metabolic abnormality in stone formers? Hypercalciuria.
5. Name the four types of hypercalciuria and their serum findings. Absorptive (normal calcium, normal/suppressed PTH); renal leak (normal calcium, elevated PTH); resorptive (elevated calcium, elevated PTH); idiopathic (normal serum).
6. Why is intestinal malabsorption associated with hyperoxaluria? Fat malabsorption causes saponification of fatty acids with calcium, leaving more free oxalate available for intestinal absorption.
7. What is the most common cause of hyperuricosuria? Increased dietary purine intake.
8. Name the three RTA types, their defect, and which is most associated with stones. Type 1 (impaired H⁺ secretion — associated with stones), type 2 (impaired bicarbonate reabsorption), type 4 (impaired mineralocorticoid response / renal failure with hyperkalaemia).
9. List the causes of hypocitraturia (DIRT). Chronic diarrhoea, idiopathic, type 1 RTA, and thiazides.
10. What are the main determinants of uric acid stone formation? Low urine pH (<5.5), low urine volume, and hyperuricosuria.
11. What is the inheritance pattern of cystinuria and which amino acids are affected? Autosomal recessive (see Corrections); impaired reabsorption of cystine, ornithine, lysine, and arginine (COLA).
12. List the radiolucent stones. Uric acid, matrix, cystine (faintly), indinavir, triamterene, xanthine, and 2,8-dihydroxyadenine.
13. Which stone is associated with laxative abuse? Ammonium acid urate.
14. List the anatomic abnormalities that predispose to stones. UPJ obstruction, horseshoe kidney, caliceal diverticulum, and medullary sponge kidney.