History

Note that hypercalciuria has no significant physical examination findings and is purely a laboratory diagnosis. Important aspects of the patient’s history may include the following:

Skeletal diseases (eg, osteoporosis, Paget disease) may produce hypercalciuria.
Immobilization for various reasons (eg, postoperative, orthopedic injury, burns, intensive care, spinal cord injury, bone marrow transplants) can cause rapid bone remodeling and, hence, elevated calcium excretion; fortunately, this has become less common owing to the use of early mobilization strategies and physical therapy
Nephrolithiasis is commonly associated with hypercalciuria
Malignancy is a common cause of hypercalcemia and hypercalciuria in hospitalized patients; it usually results from bone destruction, bone reabsorption, or humoral factors such as PTH-related protein.
Human immunodeficiency virus (HIV) infection or its treatment may be associated with a higher risk of hypercalciuria in children

Medications

Certain medications, such as vitamin-D supplements and furosemide, may contribute to hypercalciuria. All loop diuretics decrease the tubular reabsorption of calcium.^[31]

Dietary and fluid intake

Many dietary factors can alter urinary calcium excretion, including the following:

Sodium chloride
Protein
Glucose
Sucrose
Magnesium
Phosphate

An inverse relationship between phosphate intake and urinary calcium excretion is observed; thus, phosphate-restricted diets result in an increase in urinary calcium excretion. With all of the other dietary items mentioned above, a direct relationship between dietary intake and urinary calcium excretion is observed.

Family history

Idiopathic hypercalciuria can run in families, as can diseases that are associated with secondary hypercalciuria. Approximately 50% of persons with kidney stones and hypercalciuria have a first-degree relative who also has hypercalciuria.

Signs and symptoms in children

In children, hypercalciuria is often associated with some degree of hematuria and back or abdominal pain, and is also sometimes associated with voiding symptoms. The standard treatment for pediatric hypercalciuria is limited to dietary or short-term medical therapy, because the patients become asymptomatic when the hypercalciuria is corrected and are often lost to follow-up.

A study involving 124 children with idiopathic hypercalciuria found that 50% of these patients had a family history of kidney stone disease. Fifty-two children developed clinical symptoms of flank or abdominal pain during the study period, but only 6 of these children had actual renal calculi. Twenty-seven children had hematuria, and 10 had incontinence. The children were treated with increased fluid intake and a reduction in dietary oxalate and sodium. Some required treatment with thiazides. All but 5 of the patients responded to therapy. Resolution of the hypercalciuria eliminated the recurrent pain in this patient population.^[32]

Another study, looking at the long-term effects of hypercalciuria in children and several possible therapies over a 4- to 11-year period, concluded that, regardless of treatment, most children with hypercalciuria eventually become asymptomatic while remaining hypercalciuric.^[33]Because limiting calcium intake in children is unwise, the recommended dietary therapy for hypercalciuria is to use a low-sodium/high-potassium diet, which normalizes the hypercalciuria in most pediatric patients.

In children with hypercalciuria, microcrystallization of calcium with urinary anions has been suggested to lead to injury of the uroepithelium. Consequently, when taking the history of the illness, attempt to identify symptoms relating to the urinary tract. Pay particular attention to the following signs and symptoms:

Dysuria
Abdominal pain
Irritability (infants)
Urinary frequency
Urinary urgency
Change of urinary appearance
Colic
Daytime incontinence
Isolated or recurrent urinary tract infections^[2]
Vesicourethral reflux^[3]

Some clinical manifestations are age dependent. For instance, irritability may be the only manifestation in infants, but a teenager may experience renal colic and hematuria.

Differential Diagnoses

Moreira Guimarães Penido MG, de Sousa Tavares M, Campos Linhares M, Silva Barbosa AC, Cunha M. Longitudinal study of bone mineral density in children with idiopathic hypercalciuria. Pediatr Nephrol. 2012 Jan. 27(1):123-30. [Medline].
Nacaroglu HT, Demircin G, Bülbül M, Erdogan O, Akyüz SG, Caltik A. The association between urinary tract infection and idiopathic hypercalciuria in children. Ren Fail. 2013. 35(3):327-32. [Medline].
Madani A, Kermani N, Ataei N, Esfahani ST, Hajizadeh N, Khazaeipour Z, et al. Urinary calcium and uric acid excretion in children with vesicoureteral reflux. Pediatr Nephrol. 2012 Jan. 27(1):95-9. [Medline].
Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009 Feb. 94(2):351-65. [Medline].
Schwaderer AL, Srivastava T, Schueller L, Cronin R, Mahan JD, Hains D. Dietary modifications alone do not improve bone mineral density in children with idiopathic hypercalciuria. Clin Nephrol. 2011 Nov. 76(5):341-7. [Medline].
Vezzoli G, Soldati L, Gambaro G. Update on primary hypercalciuria from a genetic perspective. J Urol. 2008 May. 179(5):1676-82. [Medline].
Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int. 2001 Jun. 59(6):2290-8. [Medline].
Zwart SR, Parsons H, Kimlin M, Innis SM, Locke JP, Smith SM. A 250 µg/week dose of vitamin D was as effective as a 50 µg/d dose in healthy adults, but a regimen of four weekly followed by monthly doses of 1250 µg raised the risk of hypercalciuria. Br J Nutr. 2013 Apr 18. 1-7. [Medline].
Dhayat NA, Lüthi D, Schneider L, Mattmann C, Vogt B, Fuster DG. Distinct phenotype of kidney stone formers with renal phosphate leak. Nephrol Dial Transplant. 2018 Jun 25. [Medline].
Parks JH, Coe FL, Evan AP, Worcester EM. Clinical and laboratory characteristics of calcium stone-formers with and without primary hyperparathyroidism. BJU Int. 2009 Mar. 103(5):670-8. [Medline].
Srivastava T, Alon US. Pathophysiology of hypercalciuria in children. Pediatr Nephrol. 2007 Oct. 22(10):1659-73. [Medline].
Worcester EM, Coe FL. New insights into the pathogenesis of idiopathic hypercalciuria. Semin Nephrol. 2008 Mar. 28(2):120-32. [Medline]. [Full Text].
Nesterova G, Malicdan MC, Yasuda K, Sakaki T, Vilboux T, Ciccone C, et al. 1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis. Clin J Am Soc Nephrol. 2013 Apr. 8(4):649-57. [Medline]. [Full Text].
Dimke H, Desai P, Borovac J, Lau A, Pan W, Alexander RT. Activation of the Ca(2+)-sensing receptor increases renal claudin-14 expression and urinary Ca(2+) excretion. Am J Physiol Renal Physiol. 2013 Mar 15. 304(6):F761-9. [Medline].
Vezzoli G, Terranegra A, Soldati L. Calcium-sensing receptor gene polymorphisms in patients with calcium nephrolithiasis. Curr Opin Nephrol Hypertens. 2012 Jul. 21(4):355-61. [Medline].
Pipili C, Oreopoulos DG. Vitamin d status in patients with recurrent kidney stones. Nephron Clin Pract. 2012. 122(3-4):134-8. [Medline].
Wong P, Polkinghorne K, Kerr PG, Doery JC, Gillespie MT, Larmour I, et al. Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria. Bone. 2016 Apr. 85:55-8. [Medline].
Mahyar A, Dalirani R, Ayazi P, Hamzehloo S, Moshiri SA, Khoshbakht Ahmadi N, et al. The association of hypercalciuria and hyperuricosuria with vesicoureteral reflux in children. Clin Exp Nephrol. 2017 Feb. 21 (1):112-116. [Medline].
Park SY, Mun HC, Eom YS, Baek HL, Jung TS, Kim CH, et al. Identification and characterization of D410E, a novel mutation in the loop 3 domain of CASR, in autosomal dominant hypocalcemia and a therapeutic approach using a novel calcilytic, AXT914. Clin Endocrinol (Oxf). 2013 May. 78(5):687-93. [Medline].
Lu J, Zhao X, Paiardini A, Lang Y, Bottillo I, Shao L. Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: a case report. BMC Nephrol. 2018 Jul 13. 19 (1):181. [Medline]. [Full Text].
Luyckx VA, Leclercq B, Dowland LK, Yu AS. Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. Proc Natl Acad Sci U S A. 1999 Oct 12. 96(21):12174-9. [Medline]. [Full Text].
Duffey BG, Pedro RN, Kriedberg C, Weiland D, Melquist J, Ikramuddin S, et al. Lithogenic risk factors in the morbidly obese population. J Urol. 2008 Apr. 179(4):1401-6. [Medline].
Ayoob R, Wang W, Schwaderer A. Body fat composition and occurrence of kidney stones in hypercalciuric children. Pediatr Nephrol. 2011 Dec. 26(12):2173-8. [Medline].
Domrongkitchaiporn S, Ongphiphadhanakul B, Stitchantrakul W, Piaseu N, Chansirikam S, Puavilai G, et al. Risk of calcium oxalate nephrolithiasis after calcium or combined calcium and calcitriol supplementation in postmenopausal women. Osteoporos Int. 2000. 11(6):486-92. [Medline].
Rodman JS, Mahler RJ. Kidney stones as a manifestation of hypercalcemic disorders. Hyperparathyroidism and sarcoidosis. Urol Clin North Am. 2000 May. 27(2):275-85, viii. [Medline].
Whalley NA, Martins MC, Van Dyk RC, Meyers AM. Lithogenic risk factors in normal black volunteers, and black and white recurrent stone formers. BJU Int. 1999 Aug. 84(3):243-8. [Medline].
Maloney ME, Springhart WP, Ekeruo WO, et al. Ethnic background has minimal impact on the etiology of nephrolithiasis. J Urol. Jun 2005. 173(6):2001-4.
Rodgers AL, Lewandowski S. Effects of 5 different diets on urinary risk factors for calcium oxalate kidney stone formation: evidence of different renal handling mechanisms in different race groups. J Urol. 2002 Sep. 168(3):931-6. [Medline].
Zerwekh JE. Bone disease and hypercalciuria in children. Pediatr Nephrol. 2010 Mar. 25(3):395-401. [Medline].
Leslie S. Calcium and stone disease. Savitz GR, Leslie SW, eds. The Kidney Stones Handbook. 2nd ed. Roseville, Calif: Four Geez Press; 2000. 73-94.
Corbin Bush N, Twombley K, Ahn J, Oliveira C, Arnold S, Maalouf NM, et al. Prevalence and spot urine risk factors for renal stones in children taking topiramate. J Pediatr Urol. 2013 Jan 31. [Medline]. [Full Text].
Vachvanichsanong P, Malagon M, Moore ES. Recurrent abdominal and flank pain in children with idiopathic hypercalciuria. Acta Paediatr. 2001 Jun. 90(6):643-8. [Medline].
Alon US, Berenbom A. Idiopathic hypercalciuria of childhood: 4- to 11-year outcome. Pediatr Nephrol. 2000 Sep. 14(10-11):1011-5. [Medline].
Escribano J, Balaguer A, Martin R, Feliu A, Espax R. Childhood idiopathic hypercalciuria--clinical significance of renal calyceal microlithiasis and risk of calcium nephrolithiasis. Scand J Urol Nephrol. 2004. 38(5):422-6. [Medline].
Patel ND, Ward RD, Calle J, Remer EM, Monga M. CT-Based Diagnosis of Low Vertebral Bone Mineral Density is Associated with Hypercalciuria and Hypocitraturia on Opportunistic Imaging. J Endourol. 2018 Aug 3. [Medline].
Arrabal-Polo MA, Arias-Santiago S, de Haro-Muñoz T, Lopez-Ruiz A, Orgaz-Molina J, Gonzalez-Torres S, et al. Effects of aminobisphosphonates and thiazides in patients with osteopenia/osteoporosis, hypercalciuria, and recurring renal calcium lithiasis. Urology. 2013 Apr. 81(4):731-7. [Medline].
Fellström B, Backman U, Danielson B, Wikström B. Treatment of renal calcium stone disease with the synthetic glycosaminoglycan pentosan polysulphate. World J Urol. 1994. 12(1):52-4. [Medline].
Norman RW, Scurr DS, Robertson WG, Peacock M. Inhibition of calcium oxalate crystallisation by pentosan polysulphate in control subjects and stone formers. Br J Urol. 1984 Dec. 56(6):594-8. [Medline].
Senthil D, Subha K, Saravanan N, Varalakshmi P. Influence of sodium pentosan polysulphate and certain inhibitors on calcium oxalate crystal growth. Mol Cell Biochem. 1996 Mar 9. 156(1):31-5. [Medline].
Prié D, Blanchet FB, Essig M, Jourdain JP, Friedlander G. Dipyridamole decreases renal phosphate leak and augments serum phosphorus in patients with low renal phosphate threshold. J Am Soc Nephrol. 1998 Jul. 9(7):1264-9. [Medline].
Lemann J Jr, Pleuss JA, Gray RW, Hoffmann RG. Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults [corrected]. Kidney Int. 1991 May. 39(5):973-83. [Medline].
Martini LA, Cuppari L, Cunha MA, Schor N, Heilberg IP. Potassium and sodium intake and excretion in calcium stone forming patients. J Ren Nutr. 1998 Jul. 8(3):127-31. [Medline].
Sebastian A, Hernandez RE, Portale AA, Colman J, Tatsuno J, Morris RC Jr. Dietary potassium influences kidney maintenance of serum phosphorus concentration. Kidney Int. 1990 May. 37(5):1341-9. [Medline].
Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993 Mar 25. 328(12):833-8. [Medline].
Hiatt RA, Ettinger B, Caan B, Quesenberry CP Jr, Duncan D, Citron JT. Randomized controlled trial of a low animal protein, high fiber diet in the prevention of recurrent calcium oxalate kidney stones. Am J Epidemiol. 1996 Jul 1. 144(1):25-33. [Medline].
Xu H, Zisman AL, Coe FL, Worcester EM. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013 Mar. 14(4):435-47. [Medline].
Yendt ER, Gagne RJ, Cohanim M. The effects of thiazides in idiopathic hypercalciuria. Am J Med Sci. Apr 1966. 251(4):449-60.
Howard JE, Thomas WC, Mukai T, et al. The calcification of cartilage by urine, and a suggestion for therapy in patients with certain kinds of calculi. Trans Assoc Am Physicians. 1962. 75:301-6.
Breslau NA, Padalino P, Kok DJ, Kim YG, Pak CY. Physicochemical effects of a new slow-release potassium phosphate preparation (UroPhos-K) in absorptive hypercalciuria. J Bone Miner Res. 1995 Mar. 10(3):394-400. [Medline].
Michaut P, Prié D, Amiel C, Friedlander G. Dipyridamole for renal phosphate leak?. N Engl J Med. 1994 Jul 7. 331(1):58-9. [Medline].
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001 May 10. 344(19):1434-41. [Medline].
Bushinsky DA, Laplante K, Asplin JR. Effect of cinacalcet on urine calcium excretion and supersaturation in genetic hypercalciuric stone-forming rats. Kidney Int. May 2006. 69(9):1586-92.
Charytan C, Coburn JW, Chonchol M, et al. Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis. Jul 2005. 46(1):58-67.
Dong BJ. Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. Nov 2005. 27(11):1725-51.
Lindberg JS, Culleton B, Wong G, et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J Am Soc Nephrol. 16(3). Mar 2005:800-7.
Cinacalcet: new drug. Secondary hyperparathyroidism: where are the clinical data?. Prescrire Int. 2006 Jun. 15(83):90-3. [Medline].
Strohmaier WL, Schlee-Giehl K, Bichler KH. Osteocalcin response to calcium-restricted diet: a helpful tool for the workup of hypercalciuria. Eur Urol. 1996. 30(1):103-7. [Medline].
Yousefichaijan P, Sharafkhah M, Cyrus A, Rafeie M. Therapeutic Efficacy of Hydrochlorothiazide in Primary Monosymptomatic Nocturnal Enuresis in Boys With Idiopathic Hypercalciuria. Nephrourol Mon. 2015 Sep. 7 (5):e29127. [Medline].
Lee CT, Ng HY, Lee YT, Lai LW, Lien YH. The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop or thiazide diuretics. Am J Physiol Renal Physiol. 2015 Nov 18. ajprenal.00057.2015. [Medline].
Pak CY, Odvina CV, Pearle MS, Sakhaee K, Peterson RD, Poindexter JR, et al. Effect of dietary modification on urinary stone risk factors. Kidney Int. 2005 Nov. 68(5):2264-73. [Medline].

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Table 1. Definitions of Hypercalciuria

Diet	Definition
Regular diet (unrestricted)	Women: Urinary excretion >250 mg calcium (6.2 mmol/24 h) Men: Urinary excretion >275-300 mg calcium (7.5 mmol/24 h)
Regular diet (unrestricted)	Urinary excretion >4 mg calcium (0.1 mmol) per kilogram of body weight per day Urinary concentration >200 mg calcium per liter
Restricted diet (400 mg calcium, 100 mEq sodium)	Urinary excretion >200 mg calcium per day
Restricted diet (400 mg calcium, 100 mEq sodium)	Urinary excretion >3 mg calcium per kilogram of body weight per day

Table 2. Hypercalciuria Simplified Test Guideline

Hypercalciuria Diagnosis	Urinary Calcium on 400-mg Calcium Diet (Normal = < 200 mg/24 h)	Fasting Calcium/Creatinine (mg/dL) Ratio (Normal = < 0.11)	Post–Calcium Load Calcium/Creatinine Ratio (Normal = < 0.20)
Normal	Normal	Normal	Normal
Absorptive type I	High	Normal	High
Absorptive type II	Normal	Normal	High
Absorptive type III (renal phosphate leak)	High	High	High
Renal leak	High	High	High
Resorptive (hyperparathyroidism)	High	High	High

Table 3. Calcium-Loading Test Interpretation Guide

Criteria	Absorptive Type I Vitamin D–Dependent (Classic Form)	Absorptive Type I Vitamin D–Dependent (Variant Form)	Absorptive Type II Dietary Calcium Responsive	Absorptive Type III (Renal Phosphate Leak)	Renal Calcium Leak	Resorptive
Urinary calcium on regular diet^*	High	High	High	High	High	High
Urinary calcium on low-calcium diet^†	High	High	NL	High	High	High
Urinary calcium fasting^‡	NL	High	NL	High	High	High
Urinary calcium after 1-g calcium load^§	High	High	NL	High	High	High
Serum PO₄ (fasting)	NL	NL	NL	Low	NL or high	Low
Serum calcium (fasting)	NL	NL or high	NL	NL or high	NL or low	High
Serum PTH	NL or low	NL or low	NL	Low	High	High
Serum PTH after 1-g calcium load	NL or low	NL or low	NL	Low	High	High
Serum vitamin D-3 (calcitriol)	NL	High	NL	High	High	High
Fasting normocalciuria while on ketoconazole	No	Yes	No	Yes	No	No
Bone calcium density	NL	NL or low	NL	NL or low	Low	Low
NL = normal; PO₄ = phosphate; PTH = parathyroid hormone. ^* Regular diet is unrestricted calcium and sodium intake. Normal upper limit calciuria is < 4 mg/kg body weight per day. ^† Low-calcium diet is 400 mg calcium and 100 mEq of sodium per day. Normal upper limit calciuria is < 200 mg/day. ^‡ Fasting is a 12-hour fast. Normal upper limit is < 0.11 mg calcium/mg creatinine. ^§ After 1-g calcium load, normal upper limit is < 0.20 mg calcium/mg creatinine.

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Author

Stephen W Leslie, MD, FACS Founder and Medical Director, Lorain Kidney Stone Research Center; Associate Professor of Surgery, Creighton University School of Medicine, Chief of Urology, Creighton University Medical Center

Stephen W Leslie, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, National Kidney Foundation, Ohio State Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Sahar Fathallah-Shaykh, MD Associate Professor of Pediatric Nephrology, University of Alabama at Birmingham School of Medicine; Consulting Staff, Division of Pediatric Nephrology, Medical Director of Pediatric Dialysis Unit, Children's of Alabama

Sahar Fathallah-Shaykh, MD is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Interim Chair, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Acknowledgements

Sahar Fathallah-Shaykh, MD Assistant Professor in Pediatric Nephrology, University of Alabama at Birmingham School of Medicine; Consulting Staff, Division of Pediatric Nephrology, Medical Director of Pediatric Dialysis Unit, Children's of Alabama

Sahar Fathallah-Shaykh, MD is a member of the following medical societies: American Society of Nephrology and American Society of Pediatric Nephrology

Disclosure: Medscape Reference Honoraria Other

Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine

Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Eastern Society for Pediatric Research, Federation of American Societies for Experimental Biology, International Society of Nephrology, NationalKidneyFoundation, New York Academy of Sciences, Renal Physicians Association, Sigma Xi, and Society for Pediatric Research