John J. Pahira, MD
BASICS
DESCRIPTION
• Deposition of calcium salts in the urinary tract may result in a urinary calculus.
• Ca oxalate in its pure form or mixed with Ca phosphate (hydroxyapatite) is the most common type of calculus in industrialized countries.
EPIDEMIOLOGY
Incidence
• US annual stone incidence: 16.4/10,000
• Male > Female (3:1–2.0)
• Age of peak incidence: 20–40 yr
• 1 in 8 men, 1 in 20 women lifetime risk
• Stone incidence by composition: Ca oxalate 30–56%; mixed Ca oxalate and Ca phosphate: 11–31%
Prevalence
• 10–15% US prevalence of stones
• Lifetime prevalence of kidney stone disease is estimated at 1–15%, with the probability of having a stone varying according to age, gender, race, and geographic location.
RISK FACTORS
• See also Section II: “Urolithiasis, Risk Factors”
• Intrinsic: Polygenic defect; hypercalciuria inherited as autosomal dominant trait; white males; other illnesses: (IBD, etc.), elevated PTH, medullary sponge kidney, recurrent UTI
• Anatomic: UPJ obstruction, horseshoe kidneys
• Extrinsic risk factors: Geography/climate
• Diet: Elevated dietary protein, oxalates, refined sugars, and Ca, and low fiber intake; high salt intake increases Urinary Calcium (UCa)
• Water intake: Low consumption increases risk
• Occupation: Sedentary occupations
Genetics
• Ca oxalate: Multifactorial; hypercalciuria an autosomal dominant trait
• Idiopathic hypercalciuria: 5–10% of normals and 30–60% with Ca nephrolithiasis
• Familial tendency to form stones
PATHOPHYSIOLOGY
Hypercalciuria may be heterogeneous.
• Normocalcemic hypercalciuria (idiopathic hypercalciuria): 30–60% of Ca oxalate stones
• AH: Intestinal hyperabsorption of Ca:
– Hypercalciuria: Increased filtered load and decreased renal tubular reabsorption due to decreased PTH
• Renal loss of Ca compensates for absorption, maintains normal (SCa)
– Hypercalciuria: >4 mg/kg weight/24 hr on random diet (>250 mg/24 hr), OR >200 mg/24 hr after 1 wk diet to 400 mg Ca and 100 mEq Na/d (1)
– AH type I: Uncommon, most severe form; persistent hypercalciuria >250 mg/24 hr on random diet or restricted diet with normal SCa and normal or slightly decreased PTH level; 2-hr fasting UCa normal.
– AH type II: Most common, mild form; hypercalciuria >250 mg/24 hr on random diet but normo-calciuria on Ca/Na-restricted diet, normal SCa and PTH
– AH type III: Vitamin D–dependent hypercalciuria, renal phosphate “leak”; low serum phosphate, elevated urinary phosphate, and Ca-enhanced Vitamin D3 synthesis by the kidney leads to increased intestinal Ca absorption
• Renal hypercalciuria (renal leak):
– Impaired renal tubular reabsorption of Ca; decreased in SCa; elevated PTH; elevated vitamin D3, and increased intestinal hyperabsorption
– SCa normal, mild secondary elevated PTH
– UCa elevated on both random and restricted diets; 2-hr fasting UCa elevated
• Resorptive hypercalciuria:
– Primary elevated PTH; elevated SCa and UCa secondary to increased PTH secretion, causing excessive resorption of bone and an increased intestinal absorption of Ca due to increased PTH and increased renal synthesis of vitamin D3
– 2-hr fasting UCa is elevated
• Unclassified hypercalciuria:
– Hypercalciuria with normal SCa, normal PTH, and elevated 2-hr fasting UCa
– Na cellulose phosphate may help distinguish AH by eliminating problem of inadequate dietary preparation prior to fast and load Ca studies; renal hypercalciuria by reducing the suppressive effect of absorbed Ca on parathyroid stimulation
• Other causes Ca oxalate stones:
– Hyperuricosuria (urinary uric acid >600 mg/24 hr); only abnormality in 10% of Ca stones; up to 40% of Ca stone-formers with other physiochemical abnormalities
– May initiate Ca oxalate stones by direct induction of heterogeneous nucleation of Ca oxalate crystals, or by absorption of certain macromolecular inhibitors
• Hyperoxaluria:
– Urinary oxalate >45 mg/24 hr
– Mild hyperoxaluria (45–80 mg/24 hr) is as important a risk factor for idiopathic Ca oxalate stones as hypercalciuria and is found in 37% of patients with Ca oxalate stones
– Activity of stone disease correlates better with level of urinary oxalate than Ca.
– Most common: Intestinal hyperabsorption of oxalate: Intestinal resection (enteric hyperoxaluria), IBD, celiac, gastric/small bowel resection; JI bypass
– Bile salts and fatty acids increases large-bowel oxalate absorption.
– Fat malabsorption causes Ca to complex with bile acids and form Ca soap, which decreases free Ca in the intestinal lumen, which can complex with oxalate, and decrease oxalate for absorption.
– Stone formation due to hyperoxaluria but also contributed to by low-volume urinary output, low citrate secondary to hypokalemia, chronic metabolic acidosis
– Low magnesium levels may be secondary to intestinal malabsorption.
– Primary hyperoxaluria type I:
Autosomal recessive, defect of AGT
Elevated urinary oxalic, glycolic, glyoxylic acids
Clinically, nephrocalcinosis, tissue deposition of oxalate, and renal failure, with death by age 20 yr if untreated
2/3 have undetectable AGT on liver biopsy; glyoxylate oxidized to oxalate
– Primary hyperoxaluria type II:
Rare (21 cases) deficiency of d-glycerate dehydrogenase and glyoxylate reductase
Elevated urinary oxalate and glycerate; nephrocalcinosis and renal failure
– Dietary hyperoxaluria:
Excess oxalate-rich foods (dark green vegetables, tea, nuts, concentrated fruit juices, chocolate); vitamin C >1000 mg/d
– Pyridoxine (vitamin B6) deficiency, ethylene glycol toxicity, hepatic conversion to glycoaldehyde and glycolic acid, methoxyflurane anesthesia, converted in liver to oxalate
– Hypocitraturia:
Citrate <220 mg/24 hr; sole abnormality in 10%; 15–60% with other Ca stones causes
Acidosis most important factor in hypocitraturia; decreases urinary citrate secondary to increased renal tubular reabsorption and decreased synthesis
Causes of metabolic acidosis: IBD, chronic diarrhea; thiazide-induced hypokalemia, and intracellular acidosis; purine-rich diet (high acid-ash); strenuous exercise (lactic acid); RTA (type I, distal); increased Na intake. UTI with bacteria-degrading citrate decreases urinary Ca salts by forming soluble complexes with Ca.
• Hypomagnesuria:
– Urinary Mg <50 mg/24 hr; coexists with hypocitraturia in 2/3 and with low urine volume (<1 L/24 hr) in 40%
– Pathogenesis is not known; may be dietary (IBD and malabsorption)
ASSOCIATED CONDITIONS
IBD, chronic pancreatitis, chronic diarrhea, elevated PTH, medullary sponge kidney, UTIs
GENERAL PREVENTION
See “General Measures” below
DIAGNOSIS
HISTORY
• See “Flank Pain” and “Urolithiasis, General.”
• Review stone history, family history, and the intrinsic and extrinsic risk factors noted earlier
PHYSICAL EXAM
See “Flank Pain” and “Urolithiasis, General.”
DIAGNOSTIC TESTS & INTERPRETATION
Lab (1)
• Abbreviated protocol for low-risk single-stone formers (history, dietary habits, basic metabolic panel including Ca, PTH, and uric acid, urinalysis/pH, radiologic imaging, stone analysis)
• A comprehensive metabolic evaluation (with Ca fast/ load test) in recurrent stones and increased stone risk can be replaced by a simple evaluation (metabolic panel and 1–2 24-hr urines):
– 24-hr urine (volume, Ca, Cr, oxalate, citrate, Na, phosphate, magnesium, pH, uric acid, sulfate)
– Data best on a diet at least 1 month after stone passage or 1 wk after IVP studies
– D/C drugs that may affect the tests (vitamins, antacids, diuretics, allopurinol, etc.)
Imaging
• CT: Most sensitive
• US, KUB, Excretory Urography (ExU)
• MRI not useful for calcifications/urinary calculi
Diagnostic Procedures/Surgery (2)
• In deciding which stone-formers require a metabolic evaluation consider the following:
– 80–90% have predisposing urinary abnormality or underlying disease identified.
– Treatment program is to be maintained for life.
– 50–60% patients pass only 1 stone/lifetime.
– Involve your patient in the decision to perform a workup; explain risk and benefits.
• Criteria for metabolic evaluation:
– Anatomic abnormality; family history of stones; history of gout or major stone complications; history of metabolic stone (uric acid or cystine), infection stone (struvite), pure Ca phosphate stone (RTA or elevated PTH)
– Metabolically active (x-ray evidence of new stone or stone growth in the past year or the documented passage of a new stone or gravel)
Osteoporosis or pathologic skelet al fracture
Recurrent stone formation
Renal insufficiency
Significant number of risk factors
Solitary kidney; age at onset <20 yr
Pathologic Findings
• Stone analysis: Varying percent composition from Ca oxalate and/or Ca phosphate
• Crystals: Ca oxalate monohydrate (dumbbell/hourglass), Ca oxalate dehydrate (envelope/bipyramidal), Ca phosphate-apatite (amorphous)
DIFFERENTIAL DIAGNOSIS
• Hypercalcemia: Primary elevated PTH, RTA, vitamin D excess, immobilization, sarcoidosis, metastatic malignancies, milk-alkali syndrome, hyperthyroidism, myxedema, adrenal insufficiency, furosemide administration
• See: “Section I Filling Defect-Upper Urinary Tract.”
• See: Section I “Flank Pain”
TREATMENT
GENERAL MEASURES
• Treat active UTI.
• Medical expulsion therapy for a symptomatic ureteral stone (1)[C] (See “Urolithiasis, General”)
• Prevention tailored to patient need.
• 1st-time stone-formers at low risk for recurrence should follow a conservative approach.
• Conservative treatment is appropriate for all stone-forming patients, regardless of cause.
• High fluid intake, daily urine output of 2 L; Na and oxylate restriction
• Restrict protein (8 oz meat/chicken/fish/day)
• Vitamin C <2 g/d
• Avoid excess Ca intake. 1 serving with each meal acceptable; avoid late at night
• Ca citrate: “Stone-friendly” supplement
• Avoid stone-provoking drugs: Vitamin D, antacids, furosemide, uricosurics, triamterene
MEDICATION (3)
First Line
• Absorptive hypercalciuria type I:Thiazide (not a selective therapy for AH as does not decrease intestinal Ca; limited long-term effect):
– Hydrochlorothiazide 25–50 mg b.i.d.
– Consider K citrate (20 mEq b.i.d.)
– Alternates: Indapamide 1.25–2.5 mg/d or chlorthalidone (25–50 mg/d):
– Restrict dietary oxalate, Na to 2000 mg/d
– Magnesium supplementation
• AH type II: Moderate Ca restriction (600 mg/d or 1–2 servings dairy/d); Na restriction; thiazide if not effective; K citrate supplementation
• AH type III: orthophosphate (Neutra-Phos-K) 250–500 mg tid/qid
• Renal hypercalciuria: Thiazide to increase tubular Ca reabsorption; hydrochlorothiazide 25–50 mg b.i.d.; Indapamide 1.25–2.5 mg/d, Chlorthalidone 25–50 mg/d, K citrate supplementation (Polycitra K syrup 15–30 mL b.i.d.; Polycitra K crystals 1 packet b.i.d.; Urocit K 10–20 mEq b.i.d.); Na restriction (2 g Na diet; keep urinary Na <100 mg/d)
• Hyperuricosuric Ca nephrolithiasis: Increase fluid intake; reduce dietary purine (eg, red meat); urinary alkalization (pH 6.5–7.0), K citrate; reduce endogenous uric acid production (allopurinol 300 mg/d); if serum uric acid >8 mg/dL, or if urinary uric acid >800 mg/24 hr
• Hypocitraturic Ca nephrolithiasis: K citrate, increases intracellular pH, which increases citrate production
• Hyperoxaluria: High fluid intake; low-oxalate diet; (see http://ohf/diet.html) K citrate (60–120 mEq/d), Ca supplementation (Ca citrate, TUMS); therapy to control diarrhea. Fish oil and probiotics may help reduce oxalate excretion.
• Type I RTA: K citrate
Second Line
Absorptive hypercalciuria type I: Na cellulose phosphate out of favor (GI effects); use if UCa >500 mg/d; 2nd line only
SURGERY/OTHER PROCEDURES
See “Urolithiasis, Adult, General.”
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Untreated recurrence for Ca oxalate stones: 10% at 1 yr, 35% at 5 yr, 50% at 10 yr
• Medical therapy: Decreases new stone formation; remission >80%, and >90% recurrence reduction
COMPLICATIONS
• Obstructing calculus: sepsis and/or progressive renal damage.
• Un-obstructing calculus: May sometimes grow and cause obstruction, deterioration of renal function.
FOLLOW-UP
Patient Monitoring
• Provide patients with appropriate written dietary hand-outs
• Patients with recurrent stones on medical therapy require periodic monitoring:
– Urine analysis, urine pH
– Serum chemistry if warranted
– 24-hr urine collection
– KUB, US, or CT
Patient Resources
Urology Care Foundation: http://www.urologyhealth.org/urology/index.cfm?article=148
REFERENCES
1. Pak CYC, Kaplan R, Bone H, et al. A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias. N Engl J Med. 1975;292:497.
2. Preminger GM, Tiselius HG, Assimos DG, et al. 2007 AUA guidelines for the management of ureteral calculi. J Urol. 2007;178(6):2418–2434.
3. Preminger GM. Medical management of urinary calculus disease. Part I and II AUA Update, Volume XIV, Lesson 5 & 6, 1995.
ADDITIONAL READING
Lange JN, et al. Metabolic Evaluation and Medical Management of the Calcium Stone Former. AUA Update, Vol. 31, Lesson 22, 2012.
See Also (Topic, Algorithm, Media)
• Hypercalcuria
• Metabolic Stone Evaluation (24 Hour Urine Studies)
• Oxalate, Dietary
• Urolithiasis, Adult, General
• Urolithiasis, Calcium Oxalate/Phosphate Image 
CODES
ICD9
• 275.40 Unspecified disorder of calcium metabolism
• 592.0 Calculus of kidney
• 592.9 Urinary calculus, unspecified
ICD10
• E83.52 Hypercalcemia
• N20.0 Calculus of kidney
• N20.9 Urinary calculus, unspecified
CLINICAL/SURGICAL PEARLS
• A family history of nephrolithiasis is important risk when deciding on a metabolic work-up.
• A slight increased PTH is best indication of renal leak hypercalciuria with normal SCa and persistent hypercalciuria on a restricted diet.
• When starting on a thiazide for hypercalciuria, it is important to check serum calcium in 2–4 wk to rule out an occult hyperparathyroidism.
• Accurate 24 hr urinary uric acid cannot be done until the patient is placed on urinary alkalization as acidic urine can cause uric acid to precipitate out of solution causing underestimation.