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Epidemiology, etc

• 1/11 (9%) people will make a stone (or more) in their lifetimes
• After a stone episode, up to 50% will have another stone episode within 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

Stone Forming Factors

Oxalate: Component of most common stone type (CaOx). Only 20% come from diet, no benefit in avoiding oxalate-containing foods unless urine tests specifically show hyperoxaluria. Vitamin C (absorbic acid) is converted to oxalate, so high levels can increase stone formation.

Uric acid: can act as a nidus for CaOx stone formation. Urinary precipitation affected more by urinary acidification than uric acid levels.

Citrate: Main stone inhibitor. Inhibited by high acid foods (meat, cheese, eggs). Fruit and veggies contain the most citrate and have lowest acid load.

General Stone Prevention

1. Drink more water: maintain UOP 2-3L to dilute salts and other stone forming agents, do not need to titrate to color
2. Eat less salt: salt reabsorption in the tubule decreases calcium reabsorption, limit salt intake to < 2.3g daily (100mEq)
3. Eat less meat: protein = amino acids -> high urinary acid load, all meat (mammal, bird, fish, etc) are equal, can also increase calcium excretion
4. Oxalate-containing foods: only avoid if proven hyperoxaluria, likely due to enteric causes
5. Vitamin C (absorbic acid): can be converted to oxalate, avoid high doses

Which fluids are best?

• Volume is key - maintain UOP > 2.5L/d
• Water is best - dilutes urinary solutes
• Dark colas (contains phosphoric acid) are bad, and avoid other sugar-sweetened beverages
• Caffeinated drinks (coffee, tea) are fine
• Alcohol (wine, beer, etc) are fine

What's the deal with juice

Citrus juice contains citric acid, which is converted to citrate and bicarbonate

Grapefruit juice has the highest citrate level (197.5mEq/L)

Grapefruit and orange juice both contain potassium in addition to citrate, but lemon juice does not

Calcium supplements, yes/no?

Decreased calcium leads to increased oxalate gut absorption. Calcium supplementation increases calcium stone risk. Therefore, take supplements only if low calcium to maintain the normal range.

Workup after 1st Time Stone Formation

Medical History

• DM/obesity: insulin resistance impairs ammonium excretion, leading to low urine pH and uric acid stones
• Gout: causes hyperuricosuria
• RTA Type I (distal):
• Hyperthyroid:
• HyperPTH: causes hypercalcemia and hypercalciuria
• GI malabsorptions: increase risk for decreased calcium absorption (complexed to fats) and subsequent increased oxalate absorption (normally complexes with calcium and not absorbed)

Medications

Mineral Metabolism Workup

Indications

Components

• Blood: electrolytes (BMP), Ca, Phos, Vit D, PTH (if hypercalcemia)
• 24hr Urine (see next section)
• Stone analysis: to assess for unusual stone types

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

24hr Urine Collection

Measured variables

• Volume
• 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 -> decreased proximal tubule sodium resorption -> decreased distal tubule calcium resorption
• Citrate: complexes with calcium, can be converted to bicarbonate, decreased levels (< 450-550mg/d) 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
• Uric Acid: increased levels (> 800mg/d) create nidus for CaOx crystallization, but main determinant for precipitation is pH, not uric acid level
• pH: low pH 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)

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

Management based on metabolic workup parameters

Other random yet specific findings

• Distal RTA (Type I): hypocitraturia + elevated urinary pH + hypokalemia + hypochloremia, treat with potassium citrate and hydration
• Cystinuria: saturated at 250mg/L, sodium nitroprusside turns purple in presence of cystine, treat with hydration and alkalinization
• Struvite: urease-forming bacteria (mainly Proteus) create alkaline urine and precipitate MgNH4Phos (struvite) and CaCarb-apatite
• Ammonium acid urate: associated with laxative abuse

Medications

Thiazide Diuretics

• Mechanism: distal tubule calcium resorption, sodium excretion
• Indications: hypercalciuria, calcium stones
• Side effects: hypokalemia (may need supplements), hyperuricosuria, hypercalcemia, hyperglycemia, hypocitraturia (secondary to intracellular acidosis), tachyphylaxis
• Dosing: HCTZ 25mg BID, Chlorthalidone 25mg QD, Indapamide 2.5mg QD

Potassium Citrate (KCit)

• Mechanism: increases urinary citrate, alkalinizes urine
• Indications: calcium stones, low urinary citrate, Type I RTA, chronic diarrhea (use liquid form), thiazide-induced hypocitraturia
• Side effects: GI symptoms, hyperK (requires regular monitoring), increased CaPhos risk, wax coating passes in stool
• Dosing: 20mg BID-TID

Calcium supplements

• Mechanism: prevents oxalate absorption, maintains normocalcemia
• Indications: hypocalcemia, hyperoxaluria - test on and off supplementation
• Side effects: increases calcium stone risk
• Dosing: 500-600mg CaCarb BID

Sodium Bicarbonate, Sodium Citrate

• Mechanism:
• Indications: KCit replacement if hyperkalemia risk
• Side effects: hypernatremia
• Dosing:

Allopurinol

• Mechanism: inhibits uric acid production
• Indications: calcium stones in setting of hyperuricosuria (> 800/day) and normal calcium, do not give for uric acid stones
• Side effects: transaminitis, rash, myalgias
• Dosing: 300mg daily

alpha-mercaptopropionylglycine (Thiola)

• Mechanism:
• Indications: cystinuria
• Side effects: transaminitis, anemia, asthenia, GI distress, rash
• Dosing: 300mg BID, titrate up PRN

Acetohydroxamic acid

• Mechanism: urease inhibitor
• Indications: struvite stones that cannot be managed surgically
• Side effects: phlebitis/DVT, hemolytic anemia (3-15%), hypercoagulable state, tremor, headache, rash, palpitations, GI distress, alopecia
• Dosing: 250mg BID-TID

Follow-Up

Labs: repeat 24hr urine 6mo after initial assessment to check for improvements, then consider checking on annual basis to assess for adherence.

Imaging: no clear evidence for long term screening, but most recommend annual KUB + renal US to assess for stone formation/growth and silent hydronephrosis.

Important/Interesting Stone Studies

Borghi 1996: Increased fluid intake (> 2L) decreases stone recurrence rates over 5 yrs compared to controls (27 vs 12%)

Borghi 2002: low calcium diet versus low protein + low salt + moderate calcium, the moderate calcium diet had a 50% reduction in stone events compared to low calcium diet

Lotan 2004: 1st time stone formers are most cost effectively managed w/ conservative therapy, but metabolic workup is more beneficial for recurrent stone formers

Sources:

• Lotan, Yair, et al. "Cost-effectiveness of medical management strategies for nephrolithiasis." The Journal of urology 172.6 Part 1 (2004): 2275-2281.
• Pearle, Margaret S., et al. "Medical management of kidney stones: AUA guideline." The Journal of urology 192.2 (2014): 316-324.
• Rule, Andrew D., et al. "The ROKS nomogram for predicting a second symptomatic stone episode." Journal of the American Society of Nephrology 25.12 (2014): 2878-2886.