Hypercalciuria

HYPERCALCERUIA EXPLAINED

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HYPERCALCIURIA: A REVIEW OF LITERARURE
Dr. Manoj R. Kandoi
Hypercalciuria is defined as the excretion of urinary calcium in excess of 4mg/kg of body weight per day
while on a regular, unrestricted diet or excretion of urinary calcium and 100mEq sodium) diet.
Etiology: These include:
1. Absorptive hypercalciuria.
2. Renal leak hypercalciuria.
3. Resorptive hypercalciuria.
4. Renal phosphate leak.
5. Vitamin D intoxication.
6. Endocrinal disorders. Hyperparathyroidism, Addison disease and glucocorticoid excess.
7. Neoplastic conditions: Multiple myeloma, lymphoma, leukemia, metastatic bone tumors and
para-neoplastic syndromes.
8. Renal conditions: Renal tubular acidosis, Albright tubular acidosis.
9. Sarcoidosis and other granulomatous disease.
10. Prolonged immobilization.
Clinical significance:
· About 80% of all kidney stones contain calcium.
· At least one third of all calcium stone formers have clinically detectable hypercalciuria.
· Hypercalciuria results in kidney stone disease and osteoporosis.
· Besides hypercalciuria other causes of kidney stone diseases are hyperoxaluria, hyperuricosuria,
low urinary volume and hypocitraturia.
Role of dietary factors in hypercalciuria:
· Calcium intake: Dietary calcium is known to prevent absoption of intestinal oxalate. Any
increase in stone formation risk due to additional calcium intake is more than compensated for
by the reduction in oxaluria. Hence complete restriction of calcium is not advisable and
recommended intake is about 600-800mg calcium per day.
In general each 100mg of daily dietary calcium increases urinary calcium by 8mg/day in a healthy
population but raises urinary calcium by 20mg/day. 2000mg of calcium per day will result in
hypercalciuria or hypercalcemia in calcium stone formers.
· Animal protein: Excessive animal protein (>1.7g/kg of body weight) causes increased acid load in
the body which is neutralized by calcium release from skeleton which may exacerbate
hypercalciuria. Acid loading is also known to directly inhibit renal calcium reabsorption.
· Sodium content: Each 100mEg increase in daily sodium intake raises urinary calcium excretion
by about 50mg/day. It causes calcium release from bone, increases urinary calcium excretion by
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its direct effect on kidney and reduces the hypocalciuric effect of thiazide therapy in
hypercalciuria.
· Alcohol and caffeine intake: These increase intestinal urinary calcium excretion.
· Refined carbohydrate: These increase intestinal absorption of calcium.
Path physiology of absorptive hypercalciuria:
Absorptive hypercalciuria can be classified into 3 types:
Type I: It is the most severe and less common type of hypercalciuria. The variant is unresorptive to
dietary modifications such as dietary calcium restrictions but urinary calcium excretion normalizes
during periods of fasting.
Type II: This commonest variant is responsive to moderate dietary calcium restriction.
Type III: This rare variant is associated with a renal defect that causes excessive urinary phosphate
excretion with resultant hypophosphatemia. Hypophosphatemia causes activation of vitamin-D
3 which
in turn increases intestinal absorption of both calcium and phosphate. This excess calcium absorbed
leads to absorptive hypercalciuria.
Other problems to be considered: These include:
· Hypervitaminosis D
· Hypercalcemic nephropathy
· Nephrolithiasis
· Hypercalcemia
· Hyperoxaluria
· Hyperparathyroidism
· Hypophosphatemia
Laboratory studies:
1. Blood examination: This includes:
a. Serum calcium, phosphorus and alkaline phosphatase.
b. Serum electrolytes
c. Serum uric acid
d. Serum PTH essay
e. Serum vitamin D and Vitamin D3 in selected cases.
2. 24 hours urine examination: The tests usually performed are:
· Calcium
· Oxalate
· pH
· Volume
· Creatinine
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· Specific gravity
· Phosphate
· Citrate
· Sodium
Treatment approach: It essentially comprises of:
1. Full medical history with blood 24-hour urine testing.
2. Hypercalciuria should be confirmed first.
3. Rule out hyperparathyroidism (serum PTH levels) and hyposhosphatemia.
4. A therapeutic trial of dietary modification is given.
5. Laboratory tests are repeated.
6. If patient responds to dietary modification, continue the same treatment and do periodical
laboratory tests.
7. Patient not responding to dietary modification may require treatment with thiazide diuretics,
Ortho-phosphates, biphosphonates or sodium cellulose phosphate.
Dietary modifications:
1. Daily calcium intake must be limited to 600-800 mg/day.
2. Dietary oxalate intake should be reduced. Foods rich in oxalates include nuts, colas, teas, green
leafy vegetables, chocolate, vegetable products.
3. Intake of purines and animal protein should be less than 1.7gm/kg of body weight.
4. Refined sugar and salt (sodium) should be reduced to maximum possible.
5. Alcohol and caffeine intake should be restricted.
6. Water intake should be sufficient to produce at least 2 litre/day of urine.
7. Dietary fiber intake should be increased (12-24gm/day).
Medications:
1. Thiazide and related drugs: These are specially useful in patients with hypercalciuria with hyper
tension or osteoporosis. These are also indicated in renal leak hypercalciuria where these can
prevent secondary hyperparathyroidism, normalize vitamin D3 synthesis, calcium absorption
and urinary calcium excretion. In absorptive hypercalciuria, thiazide diuretics should be used
with caution as hypercalcemia may result.
Adverse effects of these drugs include precipitation of gout, dehydration, hypokalemia and
hyponatremia. Patients may report muscle aches, depression, decreased libido, generalized
weakness and malaise. Since thiazides are chemically sulfonamides, these should be used
cautiously in patients with history of sulfonamides, allergy. Drug interactions with other drugs
such as alcohol, narcotics, muscle relaxants, barbitutrates, antidiabeties, lithium and
nonsteroidal anti-inflammatory agents.
2. Orthophosphates: Orthophosphates reduce 24 hour urinary calcium excretion and increase
urinary stone inhibitors such as citrate and pyrophosphate. These are especially indicated in
cases of absorptive hypercalciuria and when thiazide cannot be used or are ineffective. The
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dosage used is 1-2.5 gm/day taken at regular intervals. The adverse effects include diarrhea,
bloating and gastrointestinal upset.
3. Biphosphonates: These are known to benefit in hypercalcemia and hypercalciuria by inhibitory
osteoclastic activity. These are especially indicated in hypercalciuric stone formers with
associated osteoporosis. These can also be in cases of hypercalciuria when other measures are
unsuccessful or poorly tolerated.
4. Sodium cellulose phosphate: The calcium binding action of sodium cellulose phosphate is due
to sodium ion exchange for calcium in intestine. The calcium is then excreted bound to the
cellulose in the stool.
The side effects of these drugs include excessive oxalate absorption (due to lack of calcium
availability for binding with oxalate) and magnesium deficiency (as cellulose phosphate also
binds with magnesium). Hence it is advisable to provide magnesium supplementation and
restrict oxalate intake.
Follow-up:
· Regular 24 hour urine testing and blood tests should be done until the hypercalciuria is
controlled and stable.
· Routine KUB x-rays are needed to find any newly formed stones.
Treatment of osteoporosis complicated with hypercalciuria:
The patient with combined osteoporosis and hypercalciuria should have the following laboratory work-
up done:
· 24 hour urine excretion levels to confirm hypercalciuria.
· Serum calcium levels to determine hypercalciuria.
· Serum PTH essay in detected cases of hypercalciuria.
Patients with hypercalciuria with no hypercalcemia do well with thiazide therapy which reduces urinary
calcium excretion and elevates serum calcium levels.
In other situations estrogen, biphosphonates are good therapeutic option.
Calcium supplementation if needed should be in the form of calcium citrate as its citrate component
limits any increased stone formation. It should be preceded by thiazide therapy to correct
hypercalciuria. The urinary calcium levels need to be monitored carefully and other risk factors such as
uric acid, hypovolumia, oxalate, magnesium etc should be optimized.
Further readings:
1. Schmiedl A, Schwille PO. Is magnesium a marker of disordered mineral metabolism in males
with idiopathic recurrent calcium urolithiasis? Observations focusing on fasting magnesiuria and
magnesiemia, protein and other substances in urine and plasma. Magnes Res. 2003 Sep;
16(3):192-205.
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2. Ardito G, Fadda G, Danese D, Modugno P, Giordano A, Revelli L, Ardito F, Pontecorvi A.
Coexistence of a parathyroid adenoma and parathyroid cyst causing primary
hyperparathyroidism. J Endocrinol Invest. 2003 Jul;26(7):679-82
3. Rogowska-Kalisz A, Tkaczyk M, Bilinska W, Nowicki M. {In Process Citation} Pol Merkuriusz Lek.
2003 Jul; 15(85):51-4.
4. Carbone LD, Bush AJ, Barrow KD, Kang AH. The relationship of sodium intake to calcium and
sodium excretion and bone mineral density of the hip in postmenopausal African-American and
Caucasian women. J Bone Miner Metab. 2003; 21(6):415-20.
5. Tajima T, Nakae J, Fujieda K. Two heterozygous mutations of CLDN16 in a Japanese patient with
FHHNC. Pediatr Nephrol. 2003 Oct 30.
6. Claverie-Martin F, Gonzalez-Acosta H, Flores C, Anton-Gamero M, Garcia-Nieto V. De novo
insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent’s disease.
Hum Genet. 2003 Nov; 113(6):480-5.
7. Ceran O, Akin M, Akturk Z, Ozkozaci T. Normal urinary calcium/creatinine ratios in Turkish
children. Indian Pediatr. 2003 Sep; 40(9):884-7.
8. Nicolaidou P, Georgouli H, Getsi V, Tsapra H, Psychou F, Matsinos YG, Zeis PM, Gourgiotis D.
Urinary excretion of endothelin-I in children with absorptive idiopathic hypercalciuria. Pediatr
Nephrol. 2003 Nov; 18(11):1157-60.
9. Carr G, Simmons N, Sayer J. A role for CBS domain 2 in trafficking of chloride channel CLC-5.
Biochem Biophys Res Commun. 2003 Oct 17; 310(2):600-5.
10. Ammenti A, Nitsch M. Hypercalciuria in osteogenesis imperfect type I. Klin Padiatr. 2003 Sep-
Oct; 215(5):283-5.
11. Schwartz AV. Diabetes Mellitus: Does it Affect Bone? Calcif Tissue Int. 2003 Oct 2.
12. Colston KW, Pirianov G, Bramm E, Hamberg KJ, Binderup L. Effects of Seocalcitol (EB1089) on
nitrosomethyl Urea-induced rat mammary tumors. Breast cancer Res Treat. 2003 Aug;
80(3):303-11.
13. Aceto G, Penza R, Coccioli MS, Palumbo F, Cresta L, Cimador M, Chiozza ML, Caione P. Enuresis
subtypes based on nocturnal hypercalciuria: a multicenter study. J Urol. 2003 Oct; 170(4 Pt
2):1670-3.
14. Negri AL, Spivacow R, Del Valle E, Fradinger E, Marino A, Zanchetta JR. Renal phosphate leak in
patients with idiopathic hypercalciuria and calcium nephrolithiasis. Urol Res. 2003 Sep 13.
15. Garcia-Nieto V, Navarro JF, Monge M, Garcia-Rodriguez VE. Bone mineral density in girls and
their mothers with idiopathic hypercalciuria. Nephron Clin Pract. 2003; 94(4):c89-93.
16. Weisinger JR. Bone mineral density in idiopathic hypercalciuria:the chicken or the egg? Nephron
Clin Pract. 2003; 94(4):c81-2.
17. Rake JP, Visser G, Huismans D, Huitema S, van der Veer E, Piers DA, Smit GP. Bone mineral
density in children adolescents and adults with glycogen storage disease type Ia: a cross-
sectional and longitudinal study. J Inherit Metab Dis. 2003; 26(4):371-84.
18. Winer KK, Ko CW, Reynolds JC, Doedy K, Keil M, Peterson D, Gerber LH, McGarvey C, Cutler GB
Jr. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing
parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003 Sep;
88(9):4214-20.
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19. Mittal RD, Kumar R, Mittl B, Prasad R, Bhandari M. Stone composition, Metabolic Profile and
the Presence of the gut-inhabiting bacterium Oxalobacter formigenes as risk factors for renal
stone formation. Med Princ Pract. 2003 Oct-Dec; 12(4):208-13.
20. Ogawa Y, Yonou H, Hokama S, Oda M, Morozumi M, Sugaya K. Urinary saturation and risk
factors for calcium oxalate stone disease based on spot and 24-hour urine specimens. Front
Biosci. 2003 Sep 1; 8:a167-76.
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