2- Epidemiology and pathophysiology of stone formation in the urinary system

Epidemiology and Pathophysiology of Stone Formation

• 12% lifetime risk of developing stones
• 2-3% risk of renal colic
• Recurrence within 2-3 years
• Men are affected three times more often than women
• Peak incidence between 30 and 50 years old
• Extrinsic factors increasing incidence: diet, lifestyle, social status, heredity, geography

Epidemiology: Intrinsic Factors

• Genetics (blacks and some native-born Israelis have lower stone formation rates)
• Family history (polygenic, with partial penetrance)
• Conditions like cystinuria, RTA
• Age and sex: males are affected more often (a ratio of 3:1)
• High androgen levels increase urinary oxalate excretion via increased liver oxalate production
• Increased urinary citrate concentration in women

Risk Factors for Recurrent Stone Formation

• Early onset of urolithiasis (especially in children/teenagers)
• Familial stone formation
• Stones containing brushite (CaHPO4•2H2O)
• Stones containing uric acid and urate
• Infection stones (solitary kidney not a primary risk factor for stone formation, but prevention of recurrence is important)

Diseases Associated with Stone Formation

• Hyperparathyroidism (5% of calcium stone cases)
• Renal tubular acidosis (partial or complete)
• Cystinuria
• Primary hyperoxaluria
• Jejuno-ileal bypass
• Crohn's disease
• Intestinal resection
• Malabsorptive conditions
• Sarcoidosis

Medications Associated with Stone Formation

• Calcium supplements
• Vitamin D supplements
• Acetazolamide (Diamox)
• Ascorbic acid in high doses (>4 g/day)
• Sulphonamides
• Triamterene (potassium-sparing diuretic)
• Indinavir

Anatomical Abnormalities Associated with Stone Formation

• Tubular ectasia (medullary sponge kidney)
• Pelvio-ureteral junction obstruction
• Caliceal diverticulum
• Ureteral stricture
• Vesico-ureteral reflux
• Horseshoe kidney
• Ureteroceles

Obesity and Stone Formation

• Obesity is an independent risk factor, particularly for women
• Obese patients have a higher propensity for uric acid calculi
• High-protein, low-carbohydrate diets can increase the risk of stone formation

Types of Stones

• 75% calcium oxalate or phosphate
• 15% phosphate-containing (most commonly struvite, i.e., magnesium ammonium phosphate)
• 5-10% uric acid
• 1% cystine
• Rarely, pure matrix and indinavir deposition

Pathogenesis of Stone Formation

• Supersaturation and precipitation (Kavanagh, UK)
• Renal tubular dysfunction (Khan, USA)
• Macromolecules (Ryall, AUS) -- the missing link between biology and chemistry

Conclusion of Pathogenesis

• Supersaturation is the key factor of stone formation, with renal tubular dysfunction and macromolecules playing important roles as secondary steps

Pathogenesis Theory

• Normally soluble materials supersaturate and begin crystal formation
• Crystals attach to damaged epithelial cells

Stone Formation Theories

• Nucleation theory
• Stone matrix theory
• Inhibitor of crystallization theory

Calcium

• About 60% of stones are calcium oxalate
• 10% are calcium phosphate
• 10% are mixed

Hypercalciuria

• Idiopathic (50% of calcium stones, absorbing too much calcium in intestines, PTH suppressed)
• Resorptive (hyperparathyroidism, increased bone resorption, also calcium stones)
• Renal (defective renal calcium reabsorption, usually proximal tubule)
• Primary hyperparathyroidism (5% of calcium stones)
• Sarcoidosis (Vitamin D excess, 1,25 dihydroxyvitamin D3-calcitriol)
• Malignancy (tumors produce PTH-related polypeptide)
• Thyroid hormone excess (bone resorption, mediated by thyroxine)

Oxalate

• End product of endogenous amino acid metabolism (glycine) and ascorbic acid synthesis (liver, ~80%)
• Freely filtered from the glomerulus
• Actively secreted by tubules
• Urinary levels variable (150–450 µmol/day)

Hyperoxaluria

• Normal dietary component (rhubarb, tea, beans, spinach = ~700 µmol/day)
• Hyperabsorption of dietary oxalate (enteric hyperoxaluria – inflammatory bowel disease, Pyridoxine (B6) deficiency)
• Genetic disorders of metabolism (>900 µmol/day)
• Exogenous sources (enteric hyperoxaluria – Ca and oxalate trapped in feces, malabsorption syndromes – Crohn's disease, increased intestinal and colonic oxalate absorption, bile salt toxicity in colon, increased colonic porosity to oxalate)

Uric Acid

• End product of purine metabolism (red meat, poultry, fish)
• Urinary solubility dependent on pH (urine pH 6.0–5.0, higher solubility in acidic urine)
• Insoluble uric acid increases with lower pH (~6x)
• Limit of solubility is ~90 mg/L
• Normal excretion: ~500–600 mg/day

Urate

• Important in calcium oxalate stones
• Epitaxial template (binds calcium oxalate and promotes crystal growth)

Uric Acid & Urate Stones

• Hard and smooth
• Multiple stones
• Appearance: yellow or red-brown
• Radiolucent (use ultrasound)

Struvite Stones

• Form in infected urine, high pH (>7)
• Bacterial urease (urea → ammonia → ammonium)
• Bacteria involved: Proteus, Klebsiella, Pseudomonas
• Composed of ammonium magnesium phosphate
• Large stones can be staghorn calculi

Therapeutic Recommendations for Infection Stones

• Surgical removal of stone material as completely as possible
• Short-term and long-term antibiotics
• Urinary acidification (ammonium chloride, 1 - 3 grams/2-3 times/day; methionine, 200–500mg, 1–3 times/day)
• Urease inhibition

Other Stones

• Cystine (COLA abnormality)
• Drug stones (triamterene, indinavir)
• Xanthine

Uncommon Stones

• Xanthine (autosomal recessive, xanthine oxidase deficiency, Xanthinuria)
• Dihydroxyadenine
• Silicate (rare in humans, high intake of magnesium trisilicate containing antacids, ingestion of sand in cattle)
• Matrix (infection by Proteus, radiolucent, matrix calculus has ~65% matrix content in calculi)

Other Uncommon Stones

• Triamterene (anti-hypertensive, used with hydroclorothiazide to spare Potassium, mostly found as a nucleus)
• Indinavir (drug to treat AIDS)
• Ephedrine / Guifenesin (cough medicines, radiolucent)

Surgical Conditions and Stone Disease

• Regional ileitis and ileal bypass surgery (increase oxalate absorption and risk of stone formation)
• Ileostomies (chronic diarrhea, bicarbonate loss, systemic acidosis, acidic urine—increase uric acid stone risk)

Explore the epidemiology and pathophysiology behind kidney stones, including intrinsic and extrinsic risk factors. Understand the impact of genetics, age, diet, and lifestyle on the likelihood of stone formation. This quiz highlights significant patterns and statistics related to stone formation and recurrence.