Hypercalciuria

Hypercalciuria is a medical term for excessive urinary calcium excretion and is generally considered to be the most common identifiable metabolic risk factor for calcium kidney stone disease (calcium nephrolithiasis) ¹. Hypercalciuria also contributes to osteopenia and osteoporosis. Its significance is primarily due to these two clinical entities: nephrolithiasis (kidney stone disease) and bone resorption. On average, hypercalciuric calcium stone formers have decreased bone mineral density than matched controls which are neither stone formers nor hypercalciuric. Even among kidney stone patients, those with hypercalciuria will have average bone calcium density measurements 5% to 15% lower than their normocalciuric peers ². Cortical bone is more affected by hypercalciuria than cortical bone. Interestingly, bone mineral density is inversely related with hypercalciuria in nephrolithiasis patients but not in patients without nephrolithiasis ³.

The definition of hypercalciuria can be a bit confusing. Traditionally, it has been defined as daily urinary calcium excretion of greater than 275 mg in men and greater than 250 mg in women ¹. This definition ignores concentration, age, renal function, and weight considerations as well as the obvious question of whether a different normal excretion amount is reasonable based solely on gender ⁴.

Hypercalciuria also can be defined as a daily urinary excretion of more than 4 mg calcium/kg body weight ¹. This definition is somewhat more useful in the pediatric age group if the child is over two years old; but in adults, it tends to allow higher urinary calcium excretions in heavier and obese individuals compared to lighter patients. One solution is to use 24-hour urinary calcium concentration (less than 200 mg calcium/liter urine is normal” but less than 125 mg calcium/liter is optimal) ⁵.

Another clinically useful definition, especially in pediatrics, is the random or spot urinary calcium/creatinine ratio (less than 0.2 mg calcium/creatinine mg is normal while less than 0.18 mg calcium/creatinine mg is optimal). Its benefit is that it does not necessarily need a 24-hour urine collection with every visit just to track hypercalciuria ⁶.

Which definition to use depends on the clinical situation and the availability of reliable 24-hour urine collection data. For optimal results, one approach is to look at all of the definitions and concentrate treatment on optimizing the worst of them. This “optimization” approach focuses less on what is normal and more on what an optimal level would be for a calcium stone forming patient. This type of optimization also can be used for other urinary chemical risk factors besides hypercalciuria ⁴.

Young children and infants tend to have higher urinary calcium excretion and lower urinary creatinine levels, so the suggested normal limits for calcium/creatinine ratios differ by age as follows ⁷:

• Up to six months of age: less than 0.8
• Six to twelve months of age: less than 0.6
• 24 months and older: less than 0.2

In children 2-12 years of age, the calcium/citrate ratio has been found to be useful clinically. A cutoff of 0.25 has been suggested meanting that those with a calcium/citrate ratio >0.25 are more likely to develop stones ⁷.

Hypercalciuria occurs in 5% to 10% of the adult population and is found in about one-third of all calcium stone formers ¹. Close relatives of hypercalciuric patients tend to have an increased rate of hypercalciuria themselves. Up to 40% of the first and second-degree relatives of hypercalciuric recurrent stone formers will also have hypercalciuria ⁸.

There are more than 30 million kidney stone patients and 1.2 million new kidney stone cases every year in the United States with one-third of them demonstrating hypercalciuria when tested.

Post menopausal women with osteoporosis and no history of kidney stones have a 20% chance of having hypercalciuria.

In children, both the incidence and prevalence of urolithiasis is increasing, particularly over the last 10 to 15 years. Hypercalciuria and hypocitraturia are the most commonly found metabolic problems identified in pediatric stone formers. The most common stone composition in children is calcium oxalate and calcium phosphate, but there is no apparent association between nephrolithiasis and obesity in the pediatric age group while there is such a linkage in adult stone formers. There also appears to be a higher incidence of hypercalciuria and hyperuricosuria in children with significant vesicoureteral reflux (VUR) compared to controls ⁷.

A recent study has connected hypercalciuric pediatric kidney stone patients with an increase in their urinary excretion of lipid metabolism/transport-related proteins. This suggests that abnormalities in lipid metabolism may be responsible or connected in some way to pediatric hypercalciuria and nephrolithiasis ⁷.

Hypercalciuria causes

The traditional way of looking at hypercalciuria includes absorptive which has increased intestinal calcium absorption, renal calcium leak which is an inherent kidney problem, resorptive as in hyperparathyroidism, and renal phosphate leak hypercalciuria. Not every patient will fall nicely into one of these categories, and a simpler classification requiring much less testing is now available based on clinical response ¹.

Hypercalciuria without any obvious cause, which is the majority of cases, is called idiopathic ⁹. 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 ¹⁰. Idiopathic hypercalciuria is diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause of the condition ¹¹. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium ¹¹.

The following are the most common types of clinically significant secondary hypercalciuria ¹¹:

• Absorptive hypercalciuria. Absorptive hypercalciuria is the most common type of excessive urinary calcium excretion. It is found in about 50% of all calcium stone forming patients. Increased gastrointestinal calcium absorption increases serum calcium levels while lowering serum Vitamin D and parathyroid hormone levels. Only about 20% of ingested calcium is absorbed, normally taking place in the duodenum. A Vitamin D dependent version of absorptive hypercalciuria can be identified by high serum Vitamin D levels ⁴.
• Renal phosphate leak hypercalciuria (also known as absorptive hypercalciuria type 3). Renal phosphate leak hypercalciuria is perhaps the most interesting from a pathophysiological point of view. A renal defect causes excessive urinary phosphate excretion which leads to hypophosphatemia. This induces higher Vitamin D activation in the kidney which increases intestinal phosphate absorption to correct the low serum phosphate. Unfortunately, the extra Vitamin D also increases intestinal calcium absorption. The extra calcium absorbed is eventually excreted in the urine resulting in hypercalciuria. This type of hypercalciuria is Vitamin D dependent and is relatively unresponsive to thiazides. The diagnosis is made by the findings of low or low-normal serum phosphate, hypercalciuria, high urinary phosphate, and high serum Vitamin D3 levels with normal serum calcium and parathyroid hormone (PTH) levels ⁴.
• Renal leak hypercalciuria. Renal calcium leak is found in about 5% to 10% of hypercalciuric stone formers. It is caused by a renal defect that causes an obligatory loss of calcium in the urine regardless of serum calcium levels or dietary calcium intake. This is usually accompanied by hypocalcemia and an increase in serum parathyroid hormone (PTH) levels. The calcium/creatinine ratio tends to be high in this condition (usually greater than 0.20), and there is an association with Medullary Sponge Kidney ⁴.
• Resorptive hypercalciuria – This is almost always caused by hyperparathyroidism. Resorptive hypercalciuria accounts for only about 3% to 5% of all hypercalciuric patients and is almost always due to hyperparathyroidism. Sustained, inappropriate, and excessive serum parathyroid hormone causes a release of calcium from the bone leading to osteopenia and hypercalcemia. Eventually, the hypercalcemia overcomes the normal parathyroid hormone effect of decreasing urinary calcium excretion, and the result is hypercalciuria (e.g., similar to spilling sugar in the urine in diabetics). This explains why hypercalciuria from hypercalcemia is less for any given elevated serum calcium level in patients with hyperparathyroidism than in other patients who are hypercalcemic ⁴.

Other causes of secondary hypercalciuria that need to be considered include the following:

• Hyperthyroidism
• Milk-alkali syndrome (excessive oral calcium ingestion)
• Renal tubular acidosis
• Sarcoidosis and other granulomatous diseases
• Vitamin D intoxication
• Glucocorticoid excess
• Paget disease
• Addison disease
• Albright tubular acidosis
• Various paraneoplastic syndromes
• Prolonged immobilization
• Induced hypophosphatemic states
• Multiple myeloma
• Lymphoma
• Leukemia
• Metastatic tumors (especially to the bone)

Pregnancy increases hypercalciuria during all three trimesters, but this does not appear to increase the risk of new stone disease as there is also an increase in kidney stone inhibitors.

High salt (sodium) intake has also been suggested as a possible cause of hypercalciuria. An increased sodium load leads to higher urinary excretion of sodium which decreases tubular calcium reabsorption resulting in hypercalciuria. While high salt intake may be a contributing factor, it is rarely the sole cause of significant hypercalciuria ⁵.

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

• 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.

A high animal protein diet will produce an acid load that causes a release of calcium from the bone and inhibition of renal tubular calcium reabsorption resulting in hypercalciuria. Again, this does not appear to be the sole causes of significant hypercalciuria ¹².

Certain medications, such as vitamin-D supplements and furosemide, may contribute to hypercalciuria. All loop diuretics decrease the tubular reabsorption of calcium ¹³.

Dent disease. Dent disease is a rare, X-linked hereditary disorder that primarily affects the proximal renal tubules resulting in hypercalciuria and proteinuria starting in childhood. It may progress from there, leading to osteomalacia, short stature, nephrocalcinosis, nephrolithiasis, hypophosphatemia and eventually renal failure. Up to 80% of affected males will develop end-stage renal failure by age 50. Vitamin D levels (1,25 (OH)2 Vit. D) are elevated or in the high normal range while parathyroid hormone levels are low. There are only about 250 families known to carry this disorder, so the incidence is quite low ¹⁴. Treatment is based on controlling hypercalciuria and preserving renal function. While this can be done with thiazide diuretics, the hypercalciuria almost always responds to dietary therapy. ACE inhibitors and citrate supplements are used in children with the disorder to help preserve renal function, but their effectiveness is unclear ¹⁴.

Wong and colleagues ¹⁵ reported that hypercalciuria was present in 91.9% of subjects on deferasirox, an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies but was not present in a control group taking an alternative iron chelator, deferoxamine.

Mahyar et al ¹⁶ reported a significantly higher frequency of hypercalciuria and hyperuricosuria in children with vesicoureteral reflux (VUR) than in a control group. These authors also observed a positive correlation between hypercalciuria and hyperuricosuria and severity of vesicoureteral reflux.

Animal studies have suggested that in some subjects, there appears to be an increased sensitivity to Vitamin D. This may be due to an increased number of 1,25 Vitamin D receptors in those individuals. These changes have not been reliably identified in humans; just in animal studies ¹⁷.

Hypercalciuria symptoms

There is no specific clinical finding of hypercalciuria itself, but it should be suspected in cases of calcium nephrolithiasis, nephrocalcinosis, hypercalcemia, hyperparathyroidism and osteopenia/osteoporosis. Hypercalciuria also can cause hematuria even without any detectable stone formation, particularly in children. The cause is thought to be from focal and microscopic tissue damage from tiny calcium crystals and focal stones that are too small to be diagnosed with standard techniques. Urinary testing makes the definitive diagnosis.

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 ¹⁸.

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 ¹⁹. 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 ²⁰
• Vesicourethral reflux ²¹

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.

Hypercalciuria diagnosis

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/day, the diagnosis of hypercalciuria is confirmed and further evaluation is warranted. In clinical practice, a 24-hour urinary calcium level of 250 mg is a useful initial threshold for determining hypercalciuria. In pediatrics, a ratio of more than 4 mg calcium/kg body weight, a random calcium/creatinine ratio of more than 0.18, or a 24-hour urinary calcium concentration of more than 200 mg/liter may be more useful. In practice, it often is used to identify whichever method gives the most abnormal reading and try to “optimize” it ⁴.

Spot urinary chemistry has shown poor sensitivity and specificity for hypercalciuria which is why the 24 hour urine test is so critical in making the diagnosis ⁵.

The calcium/creatinine and uric acid/creatinine ratios should be calculated to determine whether or not abnormalities are present. The normal calcium/creatinine ratio is less than 0.2; if the calculated ratio is higher than 0.2, repeat testing is indicated. If the follow-up results 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.

Hyperparathyroidism should be suspected in all adult hypercalciuric patients with elevated or borderline elevated serum calcium levels. It can be diagnosed simply by checking a parathyroid hormone level in those individuals ²².

Vitamin D levels can help detect Renal Phosphate Leak (where vitamin D is elevated along with high urinary but low serum phosphate levels). High vitamin D levels and possible Renal Phosphate Leak should be suspected in patients who do not respond to adequate thiazide therapy ²³.

24-Hour Urinary Calcium Test

The obvious initial laboratory evaluation for hypercalciuria is the 24-hour urinary calcium determination, which is generally recommended when patients are feeling well and on their usual diet. A 24-hour urine test is of little value when patients are hospitalized with acute stone attacks or other medical problems, since their diet and activity levels are different from the home conditions under which they formed the stones. The 24-hour urine sample should be collected in a standardized fashion.

In addition to calcium, other 24-hour urine chemistries that are usually performed in stone formers include the following (if possible, these chemistries should be performed together):

• Oxalate
• pH
• Volume
• Creatinine
• Specific gravity
• Phosphorus or phosphate
• Citrate
• Sodium
• Uric acid
• Magnesium
• Urea nitrogen or sulfate – These are increased in cases of high protein ingestion

Ensure that the laboratory performing the studies has a reliable methodology for urinary chemistry testing. In the United States, this most often requires sending most 24-hour urine tests to an outside reference laboratory. Because usually only a small portion of the total sample is actually sent, some potential errors are introduced if the urine sample is not handled properly or if the total volume is not measured and recorded accurately.

Instructions for proper 24-hour urine collection procedures must be reviewed carefully with every patient. The most intelligent patients are often the ones who rush through the instructions and misunderstand, delivering grossly inaccurate specimens.

One easy way to determine the accuracy of urine collection is to compare the total urinary creatinine collected with the expected levels. A properly performed 24-hour urine collection should show a mean urinary creatinine of 22.1 mg/kg in men and 17.2 mg/kg in women. Any values that are significantly different from the predicted ones probably represent improper or inaccurate collections.

Serum studies

Ideally, serum laboratory studies should be drawn at the same time that the 24-hour urine sample is being collected. In this way, the action of the kidneys can be viewed in the context of serum levels of these same parameters.

Minimum blood tests currently recommended for stone formers include the following:

• Calcium
• Phosphorus
• Electrolytes
• Uric acid
• Creatinine

Serum calcium studies should be repeated when initial levels are high, along with PTH levels to check for hyperparathyroidism. Serum intact PTH and ionized calcium are the most reliable in borderline cases. Vitamin D and vitamin D-3 are available in some laboratories and, although useful in select cases, are still considered investigational.

Calcium-loading test

The theoretical advantage of a formal calcium-loading test is a more precise diagnosis, which leads more quickly to definitive therapy. This is particularly useful in differentiating absorptive hypercalciuria type 1 and type 2 from renal leak hypercalciuria.

Usually, 2 separate 24-hour urine collections are gathered and analyzed for calcium while the patient is on a regular diet. This is undertaken to confirm the diagnosis of hypercalciuria, establish the baseline urinary calcium level, and determine if the degree of hypercalciuria is consistent and reproducible.

The patient is placed on a strict low-calcium diet of 400 mg of calcium and 100 mEq of sodium per day for 1 week. At the end of the week, an additional 24-hour urine sample is taken and tested for calcium and creatinine.

In the traditional diagnostic approach, a calcium-loading test is performed, with the type of hypercalciuria determined in the following ways:

• Absorptive hypercalciuria – During a defined period of fasting, patients with absorptive hypercalciuria show a significant decrease in urinary calcium excretion; patients are then administered a large oral calcium meal, with urine samples obtained periodically afterwards tending to show a great increase in the patient’s urinary calcium excretion
• Renal leak hypercalciuria – In this type, the kidney has an obligatory calcium-losing defect, so patients are expected to show relatively little effect from dietary measures alone, including fasting; following a large oral calcium meal, patients with renal leak hypercalciuria do not demonstrate as large an increase in urinary calcium as do those with absorptive hypercalciuria

In practice, however, performing the calcium-loading test is difficult, tedious, and usually reserved for selected cases in a tertiary care center or for research purposes.

Table 1. 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	Normal	High	High	High
Urinary calcium fasting‡	Normal	High	Normal	High	High	High
Urinary calcium after 1-g calcium load§	High	High	Normal	High	High	High
Serum PO4 (fasting)	Normal	Normal	Normal	Low	Normal or high	Low
Serum calcium (fasting)	Normal	Normal or high	Normal	Normal or high	Normal or low	High
Serum PTH	Normal or low	Normal or low	Normal	Low	High	High
Serum PTH after 1-g calcium load	Normal or low	Normal or low	Normal	Low	High	High
Serum vitamin D-3 (calcitriol)	Normal	High	Normal	High	High	High
Fasting normocalciuria while on ketoconazole	No	Yes	No	Yes	No	No
Bone calcium density	Normal	Normal or low	Normal	Normal or low	Low	Low

Footnote:

* 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.

Abbreviations: NL = normal; PO4 = phosphate; PTH = parathyroid hormone.

Differentiation between absorptive hypercalciuria types 1 and 2

The fasting and post–calcium-loading parameters are essentially the same in these 2 entities. The main difference is that patients with absorptive hypercalciuria type 1 still have hypercalciuria, defined as urinary excretion in excess of 200 mg of calcium per 24 hours, while on a 400-mg low-calcium diet. Patients with absorptive hypercalciuria type 2 have a less severe form of calcium hyperabsorption and are able to achieve normal urinary calcium levels while on the low-calcium diet.

Essentially, if the patient demonstrates normocalciuria on the restricted calcium diet, further testing is unnecessary because absorptive hypercalciuria type 2 is the only disorder that normalizes urinary calcium excretion on a limited oral calcium diet.

Differentiation of absorptive from renal leak hypercalciuria without a calcium-loading test

Patients with renal leak hypercalciuria tend to have relatively low serum calcium levels in relation to their serum parathyroid hormone (PTH) levels. Secondary hyperparathyroidism caused by an obligatory loss of serum calcium is a hallmark of renal leak hypercalciuria. The calcium/creatinine ratio tends to be high (> 0.20) in patients with renal calcium leak, and these individuals are more likely than other hypercalciuric patients to have medullary sponge kidney.

A trial of dietary therapy with a restricted calcium diet is relatively ineffective with renal leak hypercalciuria and is quite harmful in the long term because of possible bone decalcification, negative calcium balance, and osteoporosis. Alkaline phosphatase and cyclic adenosine monophosphate (cAMP) levels are often elevated in this condition.

Urinalysis

A urinary tract infection is suggested by the presence of leukocyte esterase, white blood cells (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 urinary pH and the presence of crystals also may help to 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, however, the presence of crystals or an abnormal pH is neither sensitive nor specific for hypercalciuria.

Thiazide challenge

Thiazides, the mainstay of pharmacologic therapy for hypercalciuria, increase serum calcium levels. Therefore, they can be used in a thiazide challenge for cases of borderline or subtle hyperparathyroidism to confirm the diagnosis. This involves the temporary use of thiazide therapy to create a controlled hypercalcemia. If the PTH levels drop, the patient is responding properly and hyperparathyroidism is unlikely. If the PTH level does not diminish as the serum calcium level rises, hyperparathyroidism can be diagnosed.

Dietary studies

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.

After initial history and laboratory testing, including serum and 24-hour urinary chemistries as outlined previously, patients with hypercalciuria undergo a short-term trial of dietary modification. (Patients with hypercalcemia and elevated PTH levels probably have hyperparathyroidism and should be treated appropriately.)

The test diet includes a moderate dietary calcium intake of about 600-800 mg/day. This corresponds to roughly 1 good calcium meal per day and possibly 1 additional dairy snack (eg, 1 glass of milk with a second small dairy serving). Restricting dietary salt, which can increase hypercalciuria, is important. Animal protein should be ingested in moderation (< 1.7 g/kg of body weight daily), and dietary fiber should be increased. Limiting dietary oxalate is also advantageous, to avoid an increase in oxaluria due to the loss of intestinal oxalate-binding sites from the reduction in dietary calcium.

The 24-hour urinary chemistries are repeated while the patient is on this modified diet. The author tests all of the urinary chemistries and not just calcium, because of the possibility of finding new chemical risk factors caused by the dietary changes. If patients have normalized their urinary calcium solely with dietary modifications, they can then be treated successfully with this method. If they still have significant hypercalciuria, patients need medical therapy, such as with thiazides, orthophosphates, sodium cellulose phosphate, or bisphosphonates.

The cause of the failure to control urinary calcium with dietary therapy is not particularly important at this point in therapy, although it most likely is a lack of effectiveness of the prescribed diet or a lack of patient compliance.

Testing should be repeated at periodic intervals to ascertain continued patient compliance and effectiveness. Once a stable, satisfactory urinary calcium level is established, periodic 24-hour urinary testing is not necessary more often than perhaps once a year for monitoring. Difficult or unresponsive cases can be referred to an appropriate expert or tertiary care center for further evaluation and treatment.

Pediatric patients

The American Academy of Pediatrics 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.

Imaging studies

Several imaging studies may be helpful in identifying underlying renal abnormalities or nephrolithiasis. Follow-up imaging may be needed to assess new formation, progression, or resolution of stones.

Ultrasonography

A good place to start is with ultrasonography of the urinary tract. This reveals most major malformations, nephrocalcinosis, and many stones.

Renal calyceal microlithiasis is seen as 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 ²⁴.

CT scanning

If urinary tract stones are still a strong consideration despite normal ultrasonographic findings, a noncontrast helical CT scan is indicated. This has been shown to be a very sensitive and specific modality for identifying renal stones. The scan may also identify low mineral bone density, based o attenuation measured in Hounsfield units at the L1 vertebral body ²⁵.

Radiography

A large proportion of stones is calcified; the stones may be revealed using plain radiography of the abdomen, but this technique may miss a significant number of those that are small or uncalcified.

Other radiographic studies may be indicated if metabolic bone disease is suspected or if a need to determine bone density exists ²⁶.

Intravenous pyelography

Medullary sponge kidney is a congenital condition that is most easily diagnosed by intravenous (IV) pyelography; no specific treatment for it exists. The condition appears as a whitish blush in the renal papilla, which is caused by the cystic dilatation of the distal collecting ducts before they empty into the renal pelvis. On CT scan, the diagnosis may require IV contrast.

Patients with medullary sponge kidney are quite likely to produce kidney stones, with about 60% developing nephrolithiasis at some point. About 12% of all stone formers are thought to have medullary sponge kidney (although the exact incidence is uncertain, ranging from 2.6-21% in various studies). Renal leak hypercalciuria is more frequently found in patients with medullary sponge kidney than in other hypercalciuric calcium-stone formers.

Hypercalciuria treatment

If serum calcium levels are normal (which rules out hyperparathyroidism), dietary calcium is moderated if excessive but is not overly restricted to avoid increased oxalate absorption and bone demineralization. A diet that is low in animal protein and salt (sodium) is recommended. Then, a repeat 24-hour urine test can be done to determine the response ²². If hypercalciuria persists, then medication (such as thiazides) likely will be needed. If thiazides fail, even after adjusting the dose and moderating sodium intake (which negates the hypocalciuric effect of the thiazides), then the patient could have renal phosphate leak hypercalciuria which does not typically respond to thiazide-type medications ⁵.

Thiazides can induce a positive calcium balance and reduce urinary calcium by up to 50%. Hydrochlorothiazide and chlorthalidone are used most often, but indapamide also can be used. The advantage of chlorthalidone and indapamide is their longer half-life as hydrochlorothiazide would need to be given twice a day. Thiazides will not be effective unless dietary salt intake is limited. For every gram of daily dietary salt decrease, 24 hour urinary calcium would be expected to drop by 5.46 mg ⁵.

Thiazides will also tend to reduce serum potassium, increase uric acid levels, and lower urinary citrate excretion. For that reason, it often is useful to add potassium citrate to these patients when they start on thiazide therapy ⁴.

When thiazides fail even at adequate dosages in patients with reasonable sodium restriction, it could be due to a Vitamin D-dependent form of hypercalciuria such as Renal Phosphate Leak. This variant can be treated with orthophosphates, which generally lower serum Vitamin D, or with ketoconazole which blocks cytochrome P450 3A4 resulting in a 30% to 40% reduction in circulating Vitamin D3 levels ⁴.

Orthophosphate therapy not only increases serum phosphate levels, which naturally lower Vitamin D3 activation, but also increases renal calcium reabsorption and urinary stone inhibitors like pyrophosphate. They also may act as gastrointestinal calcium binders to help reduce absorption. Orthophosphates can reduce urinary calcium excretion by up to 50% and may be given together with thiazides when necessary. However, they are most useful in cases where thiazides have failed or cannot be used as well as for renal phosphate leak hypercalciuria ⁵.

Amiloride, a potassium-sparing diuretic, is not a thiazide but when added to thiazides may further increase calcium reabsorption as well as minimizing potassium loss. (Amiloride is not usually recommended with potassium citrate due to the potential for hyperkalemia.) Triamterene is not recommended in stone formers as it can form triamterene calculi ²⁷.

Potassium citrate therapy will not only increase urinary citrate levels, but it may also increase renal calcium reabsorption reducing hypercalciuria ²⁸.

In children, treatment of hypercalciuria is primarily dietary, at least initially. Calcium intake should not be restricted unless it exceeds the usual recommended amount. Vitamin D supplementation should be avoided, and dietary animal protein intake should be limited to within the usually recommended limits. A 3 to 6 month trial of dietary measures alone is reasonable before resorting to thiazide medications ⁷.

Hypercalciuria prognosis

The morbidity of hypercalciuria is related to 2 separate factors; ie, kidney stone disease and bone demineralization leading to osteopenia and osteoporosis.

Kidney stones are extremely painful because of the stretching, dilating, and spasm of the ureter and kidney caused by the acute obstruction. The pain is unrelated to the size of the stone or its composition and is related only to the rapidity and degree of the obstruction. Although normally functioning kidneys are quite resistant to damage from acute obstruction, aggressive surgical treatment is necessary in certain situations, such as a solitary kidney, renal transplantation, pyonephrosis (infection proximal to the obstruction), and intractable pain not relieved by parenteral analgesics.

Bone-density loss

Hypercalciuric stone formers have been demonstrated to have a lower average bone mineral density than non–stone formers matched for age and sex. Moreover, compared with normocalciuric stone formers, hypercalciuric patients have an average bone density that is 5-15% lower ²⁹. In children with idiopathic hypercalciuria, bone mineral ̶ density measurements have consistently demonstrated Z-score reductions at the lumbar spine and, to a lesser extent, the femoral neck ²⁶.

Bone loss is worsened if patients are placed on a calcium-restricted diet, as 99% of the body’s calcium is stored in the bones. Fortunately, significant clinical bone loss is relatively rare. However, female hypercalciuric stone formers who become menopausal are at significantly greater risk of osteoporosis than their healthy female counterparts. The higher the urinary calcium excretion is, the greater the risk.

Untreated patients with an obligatory urinary calcium loss relatively unaffected by diet, as in renal leak hypercalciuria, renal phosphate leak, and resorptive hypercalciuria, develop a negative calcium balance that can result in osteopenia or osteoporosis.

Some patients may have a primary altered bone metabolism, as occurs in postmenopausal women with an estrogen deficiency. Thirty percent of hypercalciuric children already show evidence of bone loss, which suggests a metabolic disorder is responsible. Strong evidence exists suggesting that the underlying disorder causing the hypercalciuria is responsible for the bone demineralization, but other factors, such as an overly zealous dietary calcium restriction, undoubtedly play a role.

References

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