Hypercalciuria Workup

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 patient 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 easy and inexpensive.

Two distinct approaches to the laboratory evaluation of hypercalciuric patients exist: the traditional approach and the simplified clinical approach. With both, initial blood tests, such as serum calcium, creatinine, and phosphate studies, should be performed to identify patients at risk for hyperparathyroidism, renal failure, and renal phosphate leak. Once hyperparathyroidism has been excluded, the 2 approaches differ. ^[5]

In the traditional approach, an effort is made to formally study the exact cause of the hypercalciuria, ultimately establishing a more precise diagnosis and leading directly to the most appropriate therapy based on etiology.

The simplified clinical approach uses a goal-oriented focus with therapeutic trials of therapy. A precise diagnosis may not be determined by this system.

Pediatric patient approach

A directed stepwise approach is important in the evaluation of a child with symptoms or a history compatible with hypercalciuria in order 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 urinalysis, urinary calcium, creatinine, and uric acid.

Differentiation between absorptive hypercalciuria types I and II

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 I 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 II 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 II 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.

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.

In the traditional classification system, several distinct types of hypercalciuria exist, such as absorptive hypercalciuria types I, II, and III; renal leak hypercalciuria; and resorptive hypercalciuria. This classification system assumes that these hypercalciurias are separate and distinct entities that can and should be differentiated.

In clinical practice, these hypercalciuria types often overlap, and extensive testing to differentiate them is difficult, time consuming, and often clinically unnecessary, because such testing rarely affects therapy. In select cases in which a more extensive evaluation is necessary, the patient may benefit from a referral to a center with expertise in this area, but this is rarely required in routine clinical practice.

Calcium-loading test

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.

An alternate approach to the diagnosis of hypercalciuria is based on patients’ clinical responses. This simplified clinical approach is much easier and more practical for the vast majority of physicians and patients.

In this system, initial blood and 24-hour urine testing is performed, but the finding of hypercalciuria does not automatically require further testing, such as a calcium-loading test, to determine the exact etiology of the excess urinary calcium. Instead, a trial of therapy is instituted, usually based on dietary guidelines (after first screening the patient with blood tests for kidney failure, hyperuricemia, hypophosphatemia, and hypercalcemia).

The clinical response is evaluated with repeat 24-hour urine testing. If the hypercalciuria has resolved after dietary changes alone, the treatment plan is judged adequate and can be continued. If the response to dietary measures is insufficient, additional medical treatment is necessary. Blood and 24-hour urine testing is repeated at periodic intervals of 30-90 days. Longer intervals emphasize patient compliance, while shorter periods stress efficacy.

Appropriate treatment modifications are suggested until the results are stable, with acceptable urinary risk-factor levels.

Not only is the simplified clinical method much easier to perform and follow than the traditional workup, it also corresponds to what many experts actually carry out in their own clinical practices. The precise diagnosis may not always be clear, but the patient receives essentially the same treatment without the need for an inconvenient expensive test that is hard to interpret.

Advantages of the simplified approach

With the simplified approach, only a short-term trial of dietary therapy is needed to determine whether dietary modification is potentially adequate as a treatment. Medical treatment, usually beginning with thiazides, is used if dietary therapy alone is unsuccessful for any reason. Serum testing for PTH excess, hypercalcemia, and hypophosphatemia helps to identify those entities (hyperparathyroidism, renal leak hypercalciuria, renal phosphate leak) that should not be treated with dietary therapy alone.

The vast majority of hypercalciuric patients can be treated with this simplified plan. Ensuring that patients are retested while on the modified diet is important; otherwise, judging the effectiveness of the therapy or patient compliance is impossible.

Summary of the simplified approach

The simplified approach is carried out as follows:

• Complete a medical history

• Carry out initial blood and 24-hour urine testing

• Identify hypercalciuric patients

• Check hypercalcemic patients for hyperparathyroidism with PTH levels; consider a thiazide challenge test if the PTH level alone is inconclusive

• Check hypophosphatemic patients for hyperphosphaturia and possible absorptive hypercalciuria type III (renal phosphate leak hypercalciuria); verify the diagnosis by determining the vitamin D3 level or with a clinical trial of orthophosphate therapy

• Start a therapeutic trial of dietary modification treatment

• Repeat the blood and 24-hour urine tests

• If the hypercalciuria is controlled successfully with dietary modification, continue the therapy and repeat testing periodically; if dietary modification is unsuccessful, consider a trial of thiazide therapy

• Orthophosphates are typically recommended if thiazides are not tolerated well or fail to control urinary calcium levels adequately; they are particularly useful in hypercalciuric patients with elevated vitamin-D levels; patients whose hypercalciuria fails all of these therapies require further evaluation

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.

Urinary calcium, creatinine, and uric acid

Not only does this study function as a reasonable screening test to document hypercalciuria, it also reveals hyperuricosuria. 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.

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.

Similarly, if hyperuricosuria is detected (through the uric acid ̶ to-creatinine ratio), the appropriate evaluation for this condition should be initiated.

Urinary calcium/osmolality ratio

In children with decreased muscle mass, urinary calcium/osmolality ratio has been suggested as a more specific and sensitive screening test than calcium/creatinine ratio because of decreased urinary creatinine excretion in those patients. A urinary calcium/osmolality ratio (X 10) of less than 0.25 is considered to be suggestive of hypercalciuria.

Additional studies

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.

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.

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 I and type II 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.

Fasting sample

The fasting phase begins at 9 pm and continues until 7 am the following morning. The patient voids at 7 am, and the specimen is discarded. He or she is provided with an additional 400-600 mL of water to drink. For the next 2 hours, the patient continues fasting but does not urinate again until 9 am, when he/she is asked to void. The urine is collected and analyzed for calcium and creatinine. This specimen is called the fasting sample.

Post-calcium load sample

Next, the patient is administered a 1-g oral calcium load, which usually consists of an appropriate amount of calcium gluconate. All urine that is passed from this point until 1 pm, 4 hours later, is collected and analyzed for calcium and creatinine. This specimen is called the post–calcium load sample.

Measuring calcium/creatinine ratios

The calcium/creatinine ratio is measured in the urine specimen taken on the 400-mg calcium-restricted diet and in the fasting and post–calcium load samples. In healthy people, the calcium/creatinine ratio is no more than 0.11 for the fasting sample and no more than 0.20 for the post–calcium load sample.

Interpreting the calcium-loading test

Note that in this testing series, hypercalciuria is defined as the excretion of more than 200 mg of urinary calcium per 24 hours on the 400-mg calcium-restricted diet.

Absorptive hypercalciuria

Patients with absorptive hypercalciuria normalize their urinary calcium excretion while on a fasting diet but greatly increase their urinary calcium excretion after the calcium load. Therefore, their fasting calcium/creatinine ratio is 0.11 or less, but their post–calcium load samples are greater than 0.20, demonstrating an exaggerated calcium absorption and subsequent excretion.

Patients with absorptive hypercalciuria type I typically do not normalize their urinary calcium excretion to less than 200 mg per 24 hours on the 400-mg calcium restricted diet, whereas patients with type 2 hypercalciuria do demonstrate less than 200 mg of urinary calcium per day while on that same diet.

Renal leak and resorptive hypercalciuria

Patients with either renal leak or resorptive hypercalciuria are hypercalciuric regardless of oral calcium intake. Consequently, they show more than 200 mg of urinary calcium excretion per 24 hours on the calcium-restricted diet and demonstrate high calcium/creatinine ratios in both phases of the calcium-loading test.

The serum calcium level, however, can be used to differentiate between these 2 diagnoses. Patients with renal leak hypercalciuria have low serum calcium levels, whereas those with resorptive hypercalciuria, which occurs in patients with hyperparathyroidism, are hypercalcemic. Table 3, below, provides a guide to interpreting calcium-loading tests.

Table 3. Calcium-Loading Test Interpretation Guide (Open Table in a new window)

 

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 D3 levels are available in some laboratories and, although useful in select cases, are still considered investigational.)

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 (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.

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. ^[35]

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. ^[36]  

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. ^[31]

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.

Histopathologic and ultrastructural examinations using light and electron microscopy have shown significant changes in the lower urinary tracts and kidneys in chronic hypercalciuria specimens.

Transitional epithelial cells of the ureters and bladder demonstrate increased cell proliferation and apical cytoplasmic vacuole formation. These effects were found to be more prominent in the proximal urinary tract epithelial cells. Deeper structures have shown increased mitotic activity, edema, vasodilatation, and separation of collagen fibers.

In the kidney, findings include interstitial edema, vasodilatation, tubular degeneration, and vacuolization of the proximal and distal convoluted tubules.