AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hypercalciuria is defined by a 24-hour urinary calcium excretion more than 150 mg in an adult female, more than 200 mg in an adult male, or more than 4 mg/kg/d in a child who weighs less than 60 kg. In infants younger than 3 months, 5 mg/kg/d is considered the upper limit of normal for calcium excretion.

Hypercalciuria can be classified as idiopathic or secondary. Idiopathic hypercalciuria can be diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium. Elevated urinary calcium occurs by 3 primary mechanisms, as follows: (1) the filtered load of calcium is abnormally increased without an adequate compensatory increase in tubular calcium reabsorption, (2) the filtered calcium load is normal but tubular calcium reabsorption is reduced, or (3) the filtered load is increased and the reabsorbed load is reduced. A good screening test for hypercalciuria compares the ratio of urinary calcium to creatinine. To validate the screening test, an accurately timed urinalysis should be used to confirm any positive screens.

Pathophysiology

Urinary excretion of calcium is the result of the complex interplay of the GI tract, bone, and the kidney, which is regulated by multiple hormones. Hypercalciuria is believed to be a polygenic trait and is significantly influenced by diet.

Idiopathic hypercalciuria is the most common metabolic abnormality in patients with calcium kidney stones. Subjects with idiopathic hypercalciuria have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, a negative calcium balance is commonly seen in balance studies, especially in patients on a low-calcium diet. The mediator of decreased renal calcium reabsorption is unclear; it is not associated with either an increase in filtered renal calcium or altered parathyroid hormone (PTH) levels. 

An increased incidence of hypercalciuria is observed in first-degree relatives of individuals with idiopathic hypercalciuria, but it appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion. Increased tissue vitamin D response may be responsible for manifestations of idiopathic hypercalciuria in at least some patients.^{1, 2}

Frequency

United States

Hypercalciuria occurs in as many as 10% of children.

International

Incidence varies, with rates of 3-7% in Eastern Europe. Incidence and prevalence data from nonindustrialized countries are lacking; however, calcium-containing urinary stones occur in children from all parts of the world.

Race

Idiopathic hypercalciuria has no ethnic, racial, or gender predominance among children in the United States. Secondary hypercalciuria occurs in a distribution consistent with the underlying etiology.

Sex

Idiopathic hypercalciuria occurs with equal frequency in boys and girls.

Age

Hypercalciuria can occur at any age, including newborns. The peak incidence of idiopathic hypercalciuria is in children aged 4-8 years. The age distribution of children with secondary hypercalciuria reflects that observed in the underlying etiology.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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 items:

• Dysuria abdominal pain
• Irritability (infants)
• Urinary frequency
• Urinary urgency
• Change of urine appearance
• Colic
• Daytime incontinence
• Isolated or recurrent urinary tract infections (UTIs)

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.

Other important aspects of the history include the following:

• Past medical history
• • 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 is less common now after the introduction of early mobilization strategies and physical therapy.
  • Nephrolithiasis is commonly associated with hypercalciuria. According to some studies, 30-50% of adults with kidney stones have idiopathic hypercalcuria.
  • Hypercalciuria is not a rare finding among children with recurrent urinary tract infections.
  • 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.
• Diet and fluid intake
• • Many dietary factors can alter urinary calcium excretion, including intake of sodium chloride, protein, glucose, sucrose, magnesium, and 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 other dietary items mentioned above, a direct relationship between dietary intake and urinary calcium excretion is observed.
  • The definition of hypercalciuria depends on a rate of excretion of calcium and, therefore, does not depend on the amount of water that is excreted with it. However, many children have more symptoms and are more likely to develop urinary stones with highly concentrated urine.
• Family history: Idiopathic hypercalciuria can run in families, as can other diseases that are associated with hypercalciuria. Approximately one half of persons with kidney stones and hypercalciuria have a first-degree relative who also has hypercalciuria.

Physical

Perform a thorough physical examination in all children with suspected or proven hypercalciuria. Quite often, no abnormalities are detected during the physical examination, and the diagnosis is made by history and laboratory evaluation. However, some children may have signs of hypercalcemia, including hypertension, dehydration, weakness, vomiting, and abdominal pain. Moreover, many children with secondary hypercalciuria may have physical examination findings consistent with the underlying disease process, such as those observed in hyperparathyroidism, malignancy, sarcoidosis, and adrenal insufficiency.

Causes

As the name implies, the cause of idiopathic hypercalciuria is not known. Several theories have been published, and some data supports certain aspects of these theories; however, these theories cannot yet be uniformly applied to a large patient population. Studies that examined metabolic balance have reported increased absorption of calcium from the intestine. In some instances, this process has been shown to be independent of vitamin D or a result of increased gut sensitivity to vitamin D.

In other patients with hypercalciuria, the proportion of calcium excreted into the urine is higher than normal, regardless of dietary intake of calcium. In fact, some patients have been found to have higher than normal urinary calcium despite lower than normal dietary intake, suggesting decreased renal tubular reabsorption.

This renal tubular leak is possibly a result of a mutational defect in one or more ion channels. Another proposed mechanism involves an imbalance of calcium deposition and reabsorption in bone that is independent of PTH or vitamin D. In addition, a combination of these factors may contribute to the high amounts of urinary calcium observed in patients with idiopathic hypercalciuria.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Each of the following items has been associated with hypercalciuria and should be considered when evaluating a child with this disorder:

• Dent disease
• Diabetes mellitus
• Distal renal tubular acidosis
• Excessively high dietary calcium intake
• Hyperalimentation
• Hypothyroidism
• Idiopathic hypercalciuria
• Immobilization
• Medications (eg, loop diuretics, steroids)
• Metabolic acidosis
• Neoplastic disease
• Vitamin D excess
• Autosomal dominant hypocalcemia with hypercalciuria (ADHH)
• Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)

Keep in mind that, although idiopathic hypercalciuria is the most commonly diagnosed entity in the above list, it is a diagnosis of exclusion, and efforts should be made to exclude these other processes. Also, remember that hypercalcemia, for whatever reason, can give rise to hypercalciuria as the body attempts to lower serum calcium concentrations. This may represent appropriate physiologic compensation rather than true renal disease.

An even longer list of factors can produce symptoms and/or urinary abnormalities that can overlap with those observed in children with hypercalciuria. Until the diagnosis of hypercalciuria is made, consider the items listed above when evaluating a child with frequency/urgency, dysuria, and/or hematuria.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

As stated in the previous section, many different processes and disease states can produce overlapping symptoms and similar findings on urinalysis. A directed stepwise approach is important in the evaluation of a child with symptoms or a history compatible with hypercalciuria to avoid unnecessary expense, exposure to radiation, and patient discomfort. The first task is to document hypercalciuria. Looking for commonly associated urinary findings or problems that can produce similar symptoms is also easy and inexpensive. Consequently, the initial approach to any child with urgency, hematuria, or suspected hypercalciuria should include the following:

• Urinalysis: A urinary tract infection is suggested by the presence of leukocyte esterase, WBCs, nitrite, or bacteria on microscopic examination findings. A urinalysis also can identify hematuria, a common but insensitive and nonspecific finding in children with hypercalciuria. The urine pH and the presence of crystals also may help identify possible clues or an explanation of the observed symptoms. Uric acid and calcium oxalate crystals are usually seen in acidic urine, whereas calcium phosphate and carbonate crystals are usually seen in alkaline urine. Similarly to hematuria, the presence of crystals or an abnormal pH is neither sensitive nor specific for hypercalciuria.
• Urine calcium, creatinine, and uric acid: Not only does this study function as a reasonable screening test to document hypercalciuria, but it also reveals hyperuricosuria. The calcium-to-creatinine and uric acid–to-creatinine ratios should be calculated to determine whether or not abnormalities are present.
• • The normal calcium-to-creatinine ratio in children is less than 0.2. If the calculated ratio is higher than 0.2, repeat testing is indicated. One approach is to recheck the ratio at monthly intervals for 2 months. If the follow-up ratios are normal, then no additional testing for hypercalciuria is needed. On the other hand, if the ratio remains elevated, a timed 24-hour urine collection should be obtained and the calcium excretion calculated. The 24-hour calcium excretion test is the criterion standard for the diagnosis of hypercalciuria. If the calcium excretion is higher than 4 mg/kg/d, the diagnosis of hypercalciuria is confirmed and further evaluation is warranted.
  • If hyperuricosuria is detected, the appropriate evaluation for this condition should be initiated.
• Follow-up testing: Once hypercalciuria has been diagnosed, several follow-up tests should be considered to search for an underlying etiology. If excess dietary intake or gut absorption of calcium is a concern, a simple way to verify or refute this notion is to temporarily limit dietary calcium intake and retest. The American Academy of Pediatrics (AAP) policy statement recommends that the daily calcium intake equal 800 mg in healthy children aged 4-8 years and 1300 mg in healthy children aged 9-18 years. If hypercalciuria is detected, place the child on a diet consisting of one-half the recommended daily allowance of calcium for 5 days and remeasure the urinary calcium excretion. If the calcium excretion normalizes, allow the child to resume a diet with an appropriate calcium content and reassess. If the urinary calcium excretion is still elevated despite reduced dietary intake, further testing is indicated.
• Other laboratory tests: Other tests that are appropriate when trying to establish the cause of the hypercalciuria include serum vitamin D, vitamin A, phosphate, bicarbonate, creatinine, alkaline phosphatase, calcium, magnesium, pH, and parathyroid hormone levels. Freshly voided urine should be measured for bicarbonate and pH. A 24-hour urine collection also should be collected for measurement of calcium, phosphorus, sodium, and magnesium.
• Urine calcium-to-osmolality ratio: In children with decreased muscle mass, urine calcium-to-osmolality ratio has been suggested as a more specific and sensitive screening test than calcium-to-creatinine ratio because of decreased urine creatinine excretion in those patients. A urine calcium-to-osmolality ratio (X 10) of less than 0.25 is considered to be suggestive of hypercalciuria.

Imaging Studies

Several imaging studies may be helpful in identifying underlying renal abnormalities or nephrolithiasis.

• A good place to start is with ultrasonography of the urinary tract. This reveals most major malformations, nephrocalcinosis, and many stones.
• Renal calyceal microlithiasis represents the presence of hyperechoic spots smaller than 3 mm in diameter in the renal calyces. In one study, renal calyceal microlithiasis was suggested to be present in as many as 85% of children with idiopathic hypercalciuria and did not seem to indicate an increased risk of lithiasis.³
• If urinary tract stones are still a strong consideration despite normal ultrasound findings, a noncontrast helical CT scan is indicated. This has been shown to be a very sensitive and specific modality for identifying renal stones.
• Large proportions of stones are calcified and may be revealed using plain radiography of the abdomen, but this technique may miss a significant number of stones that are small or uncalcified.
• Intravenous pyelography (IVP) was widely used in the past to identify renal stones but is not used much in children anymore because of poorer image quality than CT scanning, larger radiation exposure, and potential toxicity of the contrast material. The cost is fairly equivocal.
• Follow-up imaging may be needed to assess new stone formation, progression, or resolution.
• Other radiographic studies may be indicated if metabolic bone disease is suspected or if a need to determine bone density exists. Plain radiography of the left hand or knees may be helpful to measure bone age. A dual energy x-ray absorptiometry (DEXA) scan can be used to determine bone density initially or follow bone density in children who require calcium-restricted diets.

Procedures

• Unless renal stones form and are not spontaneously passed, procedures are not usually necessary in the evaluation of children with hypercalciuria.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The goals of therapy in children with hypercalciuria should be the elimination of symptoms, prevention of renal stone formation, and preservation of kidney function.

Dietary modification is a mandatory part of effective therapy. The child should be referred to a dietitian to accurately assess daily calcium, animal protein, and sodium intake. As previously mentioned, a trial of a low-calcium diet can be done transiently to determine if exogenous calcium intake is contributing to the high urinary calcium. However, great caution should be used when trying to restrict calcium intake for long periods.

Because of the concern regarding poor bone matrix calcification and subsequent osteoporosis, no child should receive less than the daily recommended intake (DRI) of calcium for long periods without careful monitoring. If the dietary calcium is restricted to less than the DRI, bone density measurements and growth parameters should be taken at regular intervals to monitor the development of osteoporosis and growth retardation. Reducing sodium and animal protein to the DRI may facilitate lowering of urinary calcium. However, the authors recommend that great caution be used when placing any child on a diet with less than the DRI of calcium and that a dietitian be consulted for assistance. If this does not provide the desired results of symptom relief, prevention of nephrolithiasis, and normalization of calcium excretion (<4 mg/kg/d), pharmacotherapy should be initiated.

Another indication for starting medication is evidence of bone demineralization or history of previous renal stone formation despite a low calcium diet. Hydrochlorothiazide (HCTZ) and other thiazide-type diuretics are the agents most frequently used to treat hypercalciuria. These agents are discussed further in the Medication section.

Lithotripsy may be needed to remove a urinary stone that is not spontaneously passed and is associated with urinary obstruction.

Reduction of dietary calcium lowers urinary calcium but may increase urinary oxylate. The new calcium-oxylate product may result in supersaturation.⁴

Surgical Care

Surgical care is not usually necessary in children with hypercalciuria unless an underlying urological abnormality is present that predisposes a child to develop renal stones. Rarely, sonographic techniques are insufficient to remove a renal stone, and surgery is needed to relieve an obstruction.

Consultations

A pediatric nephrologist should evaluate and treat any child with proven or suspected hypercalciuria. Once hypercalciuria is diagnosed, a pediatric dietitian should be consulted to help construct an appropriate diet. In cases where urological abnormalities are detected or renal stones form without prompt spontaneous passage, a pediatric urologist should be involved in caring for the child.

Diet

Dietary modifications are important components in treating children with hypercalciuria. General guidelines that are applicable to most children with hypercalciuria include the following:

• Maintain water intake at 1500 mL/m²/d.
• Restrict dietary calcium to the DRI for age. The US Food and Drug Administration (FDA) sets the DRI (or recommended daily allowance [RDA]) by doubling the estimated daily need. This was done to ensure an adequate amount of calcium (and other vitamins and minerals) intake for growth and development.
• • Some people believe that this is an overestimation of the amount of calcium intake actually needed. In otherwise healthy children with normal urinary calcium excretion, the excess calcium is removed in the urine without consequence. However, in children who have hypercalciuria, this amount of dietary calcium may induce symptoms or renal stone formation.
  • Consequently, some health care providers believe it may be safe to use less than the DRI of calcium in children who are still having hypercalciuria and renal stone formation with normal amounts of calcium in their diet. If such a diet is used, monitoring bone mineralization and growth parameters at regular intervals is essential. Alternatively, if the desired urinary calcium excretion is not achieved with the RDI of calcium, pharmacotherapy can be initiated.
• Restricting dietary sodium may also be helpful in children with hypercalciuria. As mentioned above, a direct relationship between sodium chloride intake and urinary calcium excretion is observed. Therefore, limiting salt intake should help reduce the amount of urinary calcium. No data indicate that high salt intake alone can induce the clinical syndrome of hypercalciuria. However, evidence may show that lower sodium diets help reduce urinary calcium excretion in children who have idiopathic hypercalciuria. A good target range for dietary sodium intake is 2-3 mEq/kg/d.
• In children with a history of calcium oxalate stones, lowering dietary oxalate is indicated.
• Diets high in animal protein may produce a larger metabolic acid load in adults and contribute to stone formation. Studies in children are not available; however, protein intakes higher than the DRI are not necessary and may be harmful.

Activity

No limitations of activity are needed, but an effort should be made to ensure adequate fluid intake with increased insensible losses (eg, exercise).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Thiazide diuretics

Thiazide diuretics are used in children with hypercalciuria that is not adequately controlled with dietary modifications alone. Poor control is indicated by persistent symptoms, nephrolithiasis, or urine calcium excretion higher than 4 mg/kg/d despite the DRI of calcium, sodium, and animal protein. Thiazide diuretics are also used upon evidence of bone demineralization on diets with less than the DRI of calcium.

Thiazides work by increasing calcium reabsorption at the level of the distal nephron and, thus, lowering urinary calcium. HCTZ is the agent most commonly used, but other thiazide or thiazide-type diuretics can be used, including trichlormethiazide and chlorthalidone. Despite the common use of thiazides, no long-term clinical trials have been performed documenting their efficacy and safety in children. Parents should be notified of this and understand the risks and benefits before initiating therapy.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care is generally not required unless a severe urinary obstruction does not spontaneously resolve or unless other complications occur.

Further Outpatient Care

• Children with hypercalciuria should be followed at regular intervals by a pediatric nephrologist. Twenty-four hour urine collections for calcium clearance should be monitored at 6-month intervals. Growth parameters should be followed in all children, and bone mineralization should be measured if less than the DRI of calcium is consumed. Serum electrolytes, uric acid, and lipid panels should be monitored in children on thiazide therapy.

Complications

• Children with hypercalciuria have an increased risk of developing urinary stones, although most kids with this condition do not develop these.
• The major complications from this condition are from urinary obstruction. Otherwise, the major morbidity is from frequent enuresis, dysuria, frequency-urgency, and other inconveniences.

Prognosis

• The vast majority of children diagnosed with idiopathic hypercalciuria do extremely well. They normally have preserved renal function and can have symptom-free lives with the appropriate management. Several studies have shown that variable combinations of dietary and pharmacologic therapy can reduce duration and/or severity of symptoms significantly. In some cases, life-long therapy is required.
• The prognosis for secondary hypercalciuria depends on that of the underlying etiology, but the elevated urinary calcium usually does not contribute significantly to the morbidity or mortality of the preexisting condition.

Patient Education

• The patient must be educated on the nature of the disorder, the possible symptoms or complications that can accompany it, the possible need for dietary and pharmacologic interventions, and the ultimate prognosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• As with many conditions, failure to make a prompt and accurate diagnosis may lead to unnecessary morbidity risk for litigation.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Srivastava T, Alon US. Pathophysiology of hypercalciuria in children. Pediatr Nephrol. Oct 2007;22(10):1659-73. [Medline].
2. Worcester EM, Coe FL. New insights into the pathogenesis of idiopathic hypercalciuria. Semin Nephrol. Mar 2008;28(2):120-32. [Medline].
3. Escribano J, Balaguer A, Martin 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].
4. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. Jan 10 2002;346(2):77-84. [Medline].
5. Alon US, Berenbom A. Idiopathic hypercalciuria of childhood: 4- to 11-year outcome. Pediatr Nephrol. Sep 2000;14(10-11):1011-5. [Medline].
6. Barratt TM, Duffy PG. Nephrocalcinosis and urolithiasis. Pediatr Nephrol. 1999;1:933-45.
7. Biyikli NK, Alpay H, Guran T. Hypercalciuria and recurrent urinary tract infections: incidence and symptoms in children over 5 years of age. Pediatr Nephrol. 2005;20(10):1435-8. [Medline].
8. Burren CP, Curley A, Christie P, et al. A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges. J Pediatr Endocrinol Metab. 2005;18(7):689-99. [Medline].
9. Gonzalez C, Ariceta G, Langman CB, Zibaoui P, Escalona L, Dominguez LF, et al. Hypercalciuria is the main renal abnormality finding in Human Immunodeficiency Virus-infected children in Venezuela. Eur J Pediatr. May 2008;167(5):509-15. [Medline].
10. Heiliczer JD, Canonigo BB, Bishof NA, Moore ES. Noncalculi urinary tract disorders secondary to idiopathic hypercalciuria in children. Pediatr Clin North Am. Jun 1987;34(3):711-8. [Medline].
11. Kang JH, Choi HJ, Cho HY, et al. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis associated with CLDN16 mutations. Pediatr Nephrol. 2005;20(10):1490-3. [Medline].
12. Polinsky MS, Kaiser BA, Baluarte HJ, Gruskin AB. Renal stones and hypercalciuria. Adv Pediatr. 1993;40:353-84. [Medline].
13. Polito C, La Manna A, Cioce F. Clinical presentation and natural course of idiopathic hypercalciuria in children. Pediatr Nephrol. Dec 2000;15(3-4):211-4. [Medline].
14. Richmond W, Colgan G, Simon S, et al. Random urine calcium/osmolality in the assessment of calciuria in children with decreased muscle mass. Clin Nephrol. 2005;64(4):264-70. [Medline].

Article Last Updated: Jul 25, 2008