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Risk factors

Epidemiology

• Prevalence: 1/11 (9%) people will make a stone (or more) in their lifetimes
• Risk factors: dry/hot climate, obesity, DM (increased uric acid levels, impaired ammonium excretion)
• Recurrence: up to 50% will have another stone episode within 5-10yrs - metabolic syndrome (obesity, HTN, DM) increase stone forming risks
• ROKS nomogram: Created in 2014, predicts risk of stone formation based on patient and stone factors

Soluble increasing stone formation

• Calcium: modulated by PTH and Vitamin D, produces both CaOx and CaPhos stones
• Sodium: increased levels get reabsorbed resulting in increased calcium secretion (Na/Ca exchanger)
• Oxalate: component of most common stone type (CaOx), only 20-50% come from diet, vitamin C (absorbic acid) is converted to oxalate
• Uric acid: can act as a nidus for CaOx stone formation, urine levels affected by pH + volume + uric acid quantity, precipitation affected more by urine acidity than uric acid concentration
• Cysteine: disulfide bond results in insolube cystine

Other factors increasing stone risk

• Acidosis: increased urine calcium and phosphate, decreased citrate, increased bone breakdown
• Urease-splitting organsisms: Proteus, Klebsiella, Serratia, Staphylococcus, Morganella, Providencia, Enterobacter
• Matrix: noncrystalline material that forms nidus for stones

Factors decreasing stone formation

• Citrate: main stone inhibitor, complexes with calcium, inhibited by high acid foods (meat, cheese, eggs), fruit/veggies contain the most citrate and have lowest acid load
• Magnesium: complexes with oxalate, inhibits crystal growth
• Phosphate/pyrophosphate: complexes with oxalate, inhibits crystal growth, difficult to increase in urine
• Urea: increases uric acid solubility
• Macromolecules: GAGs (chondroitin and heparin sulfate) and glycoproteins (Tamm-Horsfall and nephrocalcin) inhibit crystal aggregation

Hypercalciuria

• Resorptive: primary hyperPTH increases bone turnover and intestinal absorption, causing hypercalcemia and subsequent hypercalciuria, treated with parathyroidectomy
• Absorptive: increased GI tract absorption of calcium
• Renal: calcium wasting via nephron leakage
• Granulomatous disease: increased 1-alpha hydroxylase (produced by macrophages) -> increased Vitamin D production, treat with steroids
• Thiazide challenge: initiation of thiazide will lead to persistent hyperPTH if primary, but hyperPTH will resolve if secondary
• Overall, no need to differentiate between types besides diagnosing hyperPTH (does not change treatments)

Anatomic risk factors

• UPJ obstruction: assocation questionable, as stone risk persists after treatment of obstruction
• Horseshoe kidney: 20% incidence, thought to be due to high ureteral insertion
• Caliceal diverticulum: combination of urinary stasis and stone forming factors
• Medullary stone kidney: unclear cause, combination of inability to acidify urine, hypercalcuria, hypocitraturia

Medication

• Increase stone risk factors: acetazolamide, topiramate, vitamin C (converted to oxalate), probenacid, antacids, chemotherapy, furosemide
• Directly precipitates as stones: triamterene, guafenesin, ephedrine, indinavir

Types of Stones

• Calcium oxalate: most common type, usually caused by dehydration, difficult to dissolve
• Calcium phosphate: common with hyperPTH, Type 1 RTA, medullary sponge kidney, carbonic anhydrase inhibitor use
• Uric acid: second most common type, usually have normal blood/urine uric acid levels, usually caused by dehydration, radiolucent on KUB, dissolve with alkalinization
• Magnesium ammonium phosphate (struvite): caused by UTI, most common cause of staghorn stones, may dissolve with acidification
• Cystine: seen in cystinuria, may dissolve with alkalinization
• Ammonium acid urate: seen with laxative abuse and IBD, as well as UTI and hypophosphatemia, may not show up on KUB
• Matrix: seen with UTI, very soft, may not show on imaging
• Indinavir: not seen on non-contrasted CT imaging

Patient evaluation

Patient history risk factors

• Personal/family history stones
• DM/obesity: insulin resistance impairs ammonium excretion, leading to low urine pH and uric acid stones
• Gout: causes hyperuricosuria
• HyperPTH: causes hypercalcemia and hypercalciuria
• Cancer, sarcoid, and granulomatous disease: increases risk for hypercalcemia through PTHrP or Vitamin D
• GI malabsorptions: increase risk for decreased calcium absorption (complexed to fats) and subsequent increased oxalate absorption (normally complexes with calcium and not absorbed)
• Type I RTA: inability to acidify urine from impaired hydrogen secretion in distal tubule, diagnosed with urine pH > 6 and hypokalemia, 75% patients form stones, confirm diagnosis with ammonium chloride loading test (unable to acidify urine after acid load)
• Chronic diarrhea and IBD: causes hyperoxaluria
• Sedentary/immobile: increased calcium absorption and excretion

"High risk" stone formers

• Large stone burden
• 2+ stone episodes
• Nephrocalcinosis
• Pediatric stone formation
• Uncommon stone types: cystine, uric acid, infection (struvite)
• Family history
• Medical conditions with increased risk: gout, IBD, hyperPTH, sarcoidosis, PCKD, RTA, medullary sponge kidney
• Solitary kidney
• Professions with high risk for stone complications

Workup components

• History: medical risk factors (see above), fluid intake, diet, medications, UTI hx
• Blood: electrolytes (BMP), Ca, Phos, Vit D, PTH (if hypercalcemia), uric acid
• UA: assess pH, urine crystals
• Stone analysis: to assess for unusual stone types

24hr Urine Collection

Patient counseling

• Indications for 24hr urine collection: high risk stone formers, abnormal labwork, or desires evaluation
• Timing: wait 1mo after stone treatment and stent removal
• Initial evaluation: obtain 1-2 tests on patient's normal diet
• Repeat evaluation: repeat on stone prevention diet, then start medications if warranted
• Follow-up evaluation: repeat 2-6mo after initial interventions, then consider annual testing

Measured variables

• Volume: < 2-3L/d increases risk for mineral precipitation and stone formation
• Calcium: increased levels (> 200mg/d) lead to increased stone formation, no need to differentiate between the three types
• Oxalate: increased levels (> 40mg/d) complex with calcium and precipitate out, can be due to increased gut absorption
• Sodium: high urinary sodium (> 150mEq/d) leads to decreased proximal tubule sodium resorption causing decreased distal tubule calcium resorption
• Citrate: decreased levels (< 450-550mg/d) result from acidosis and increase calcium stone formation
• Magnesium: can bind oxalate, underlying cause for enteric hyperoxaluria can cause decreased magnesium absorption and subsequent decreased levels (< 80/d)
• Potassium: low levels (< 20-100mg/d)
• Uric Acid: increased levels (> 600-800mg/d) create nidus for CaOx crystallization, but main determinant for precipitation is pH (not uric acid level), abnormally low uric acid + low pH may indicate uric acid stone
• pH: low pH (< 5.5) induces uric acid precipitation, elevated levels increase CaPhos formation
• Sulfate: increased levels indicates high animal protein intake
• Creatinine: indicates adequacy of collection based on expected normal value for creatinine excretion (20-25mg/kg/d for men, 15-20mg/kg/d for women)
• Cystine: normal excretion 0.4% (cystinurics excrete 100%), saturated at 250mg/L, sodium nitroprusside turns purple in presence of cystine, no need to check if initial test normal

Tips for Collection

• Make sure a day is chosen where urine can be completely collected
• Start after first morning void, and collect until morning void of following day
• Discontinue Vitamin D, calcium, antacids, diuretics, acetazolamide, and Vitamin C