Introduction
Background
Hypercalciuria, or excessive urinary calcium excretion, is the most common identifiable cause of calcium kidney stone disease. (The other significant causes include hyperoxaluria, hyperuricosuria, low urinary volume, and hypocitraturia.)
Hypercalciuria is defined as urinary excretion of more than 250 mg of calcium per day in women or more than 275-300 mg of calcium per day in men while on a regular unrestricted diet. It also can be defined as the excretion of urinary calcium in excess of 4 mg/kg of body weight per day or as a urinary concentration of more than 200 mg of calcium per liter.
An alternate definition is daily urinary excretion of more than 3 mg of calcium per kilogram of body weight or more than 200 mg of calcium per day while on a restricted (400 mg calcium and 100 mEq sodium) diet.
Table 1. Definitions of Hypercalciuria
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Table
| Diet | Definition |
|---|---|
| Regular diet (unrestricted) | Women: >250 mg calcium (6.2 mmol/24 h) Men: >275-300 mg calcium (7.5 mmol/24 h) |
| > 4 mg calcium (0.1 mmol) per kilogram of body weight per day | |
| Restricted diet (400 mg calcium, 100 mEq sodium) | 200 mg calcium per day |
| > 3 mg calcium per kilogram of body weight per day |
| Diet | Definition |
|---|---|
| Regular diet (unrestricted) | Women: >250 mg calcium (6.2 mmol/24 h) Men: >275-300 mg calcium (7.5 mmol/24 h) |
| > 4 mg calcium (0.1 mmol) per kilogram of body weight per day | |
| Restricted diet (400 mg calcium, 100 mEq sodium) | 200 mg calcium per day |
| > 3 mg calcium per kilogram of body weight per day |
Several experts, including the author of this article and Dr. Gary Curhan of Harvard, have suggested that the current definitions of hypercalciuria and several other 24-hour urinary chemistries are inadequate and may not be reliable when applied to nephrolithiasis. Available definitions are limited by the occasional inclusion of recurrent stone formers in the healthy group and by poorly defined controls. In addition, the parameters and ranges are not optimized from the point of view of kidney stone disease or production.
The data from several large databases (including the Nurses' Health Study and the Health Professional Follow-up Study) indicate that, with the current definition of hypercalciuria, a substantial proportion of controls would be defined as abnormal. The relative risk of stone production appears to be continuous, along a sliding scale, rather than dichotomous with a single arbitrary level that differentiates healthy people from those who form stones. While the gross total 24-hour urinary calcium excretion remains useful, the urinary calcium concentration is probably a more reliable dynamic indicator of stone formation risk. Further study is needed to confirm these conclusions and to possibly establish better revised 24-hour urine reference ranges for calcium and other metabolic stone risk chemistries.
The most common types of clinically significant hypercalciuria are absorptive, renal leak, resorptive, and renal phosphate leak. Each of these conditions is described in more detail later in this article. Other causes of hypercalciuria that need to be considered but are not discussed in this article include hyperthyroidism, renal tubular acidosis, sarcoidosis and other granulomatous diseases, vitamin D intoxication, glucocorticoid excess, Paget disease, Albright tubular acidosis, various paraneoplastic syndromes, prolonged immobilization, induced hypophosphatemic states, multiple myeloma, lymphoma, leukemia, metastatic tumors especially to bone, Addison disease, and milk-alkali syndrome.
About 80% of all kidney stones contain calcium, and at least one third of all calcium stone formers are found to have hypercalciuria when tested. Hypercalciuria contributes to kidney stone disease and osteoporosis, which explains the need to understand this disorder clearly.
Pathophysiology
Brief Outline of Dietary Factors
The obvious dietary advice for people who form calcium stones recurrently is to reduce the calcium content of the diet. Unfortunately, this common sense advice appears to be incorrect. Several large population studies in both men and women have shown that, within reasonable limits, patients with the highest dietary calcium levels also had the lowest rates of new calcium stone formation. Apparently, dietary calcium acts as a scavenger in the digestive tract and prevents absorption of intestinal oxalate. Any modest increase in risk of stone formation from additional calcium absorption is more than compensated for by the reduction in oxaluria. Creation of a negative calcium balance is also a risk. A modest reduction in dietary calcium, with optimal levels at about 600-800 mg of calcium per day in most hypercalciuric patients, is currently recommended. Ingestion of more than 2000 mg of calcium per day generally results in hypercalciuria and/or hypercalcemia in calcium stone formers.
Intestinal adaptation occurs with long-term, consistent calcium intake. This means that patients with persistently low dietary calcium increase their intestinal calcium absorption and those with a high calcium intake show a corresponding decrease in intestinal absorption. Fractional calcium absorption decreases with larger calcium loads, probably due to saturation of active absorption pathways. It plateaus at about 500 mg of calcium for most people. This means that an oral calcium dose is absorbed better if administered in small divided portions rather than in a single large calcium bolus. In general, each additional 100 mg of daily dietary calcium ingestion increases urinary calcium levels by 8 mg/day in a healthy population but raises urinary calcium levels by 20 mg/day in hypercalciuric patients.
Several dietary factors besides calcium can contribute to hypercalciuria. These include animal protein, sodium, alcohol, caffeine, refined carbohydrates, fiber, oxalate, and fluids. Each is reviewed in more detail below.
Excessive animal protein (>1.7 g/kg of body weight) increases the body's acid load. This additional acid load is buffered or neutralized in part by the bony skeleton, which then releases calcium into the general circulation. This extra serum calcium is eventually excreted by the kidneys into the urine, exacerbating any hypercalciuria. Acid loading also directly inhibits renal calcium reabsorption, resulting in an increase in urinary calcium excretion.
Animal protein also contributes a large purine load. Purines are the precursors of uric acid, which can form uric acid stones, lower the urinary pH, increase the overall acid load, contribute to gouty diatheses (a condition involving both stone disease and elevated uric acid levels), and generally increase urinary calcium excretion and stone formation.
Sodium intake is another significant dietary risk factor for kidney stone disease and hypercalciuria. High dietary sodium is associated with increased calcium release from bone, further contributing to any existing hypercalciuria. It also causes an increase in urinary calcium excretion through a direct effect on the kidneys and reduces or eliminates the hypocalciuric effect of thiazide therapy in hypercalciuria. Each 100-mEq increase in daily sodium intake raises urinary calcium excretion by about 50 mg/day.
Alcohol intake should be limited because ethanol reduces osteoblastic activity, lowers parathyroid hormone (PTH) levels, and contributes to osteoporosis. It also indirectly accelerates osteoclastic activity, increases urinary calcium excretion, and contributes to bone loss.
Caffeine intake also should be limited because caffeine increases urinary calcium excretion. The ingestion of 34 ounces of caffeine causes a loss of 1.6 mmol of total calcium, contributing to both hypercalciuria and osteoporosis.
Another dietary factor that affects calcium excretion is refined carbohydrates, which increase intestinal calcium absorption. Restricting dietary oxalate is necessary whenever calcium intake is limited in order to avoid a reactive absorptive hyperoxaluria caused by the decrease of intestinal oxalate-binding sites (calcium). High dietary fiber binds to free intestinal calcium, reducing its absorption. Increasing fluid (water) intake lowers urinary calcium concentrations without affecting total calcium excretion.
Brief Outline of Specific Hypercalciuria Disorders
Absorptive hypercalciuria
Absorptive hypercalciuria is by far the most common cause of excessive urinary calcium. About 50% of all calcium stone formers have some form of absorptive hypercalciuria, which is caused by an increase in the normal gastrointestinal absorption of calcium, overly aggressive vitamin D supplementation, or excessive ingestion of calcium-containing foods (milk-alkali syndrome). Calcium absorption occurs mainly in the duodenum and normally represents only about 20% of the ingested dietary calcium load.
Increased intestinal calcium absorption produces a corresponding increase in serum calcium levels. Typically, serum PTH is low or in the low-normal range in absorptive hypercalciuria because the serum calcium level generally is high. Mild or moderate absorptive hypercalciuria usually can be controlled solely with dietary measures (see Dietary treatment guidelines), but medical therapy is required in severe and resistant cases.
An interesting study in specially prepared transgenic mice suggests the possible importance of the gene encoding CLC5 (a renal chloride channel located exclusively in the kidney) to the development of hypercalciuria. The transgenic mice were produced using an antisense ribozyme targeted against CLC5 so that these mice lacked CLC5 activity. This mouse model is similar to Dent disease in humans, which is a rare X-linked inheritable disorder with reduced CLC5 activity characterized by hypercalciuria, nephrocalcinosis, nephrolithiasis, low molecular weight proteinuria, Fanconi syndrome, and renal failure. In Dent disease, the nephrolithiasis, hypercalciuria, and nephrocalcinosis are eliminated with a renal transplant from a healthy individual, confirming the renal cause of these problems.
In the mouse study, the CLC5-deprived transgenic mice had significant hypercalciuria compared to the healthy controls. Serum electrolyte levels and renal function were normal in both groups. Dietary calcium deprivation corrected the hypercalciuria in the transgenic CLC5-deficient mice, which suggests that diminished function of CLC5 is a causative factor in some types of absorptive hypercalciuria, such as Dent disease. If so, genetic therapy someday may be able to correct this disorder permanently.
Absorptive hypercalciuria can be categorized into the following 3 types:
- Type I is relatively uncommon and is the most severe type of absorptive hypercalciuria. It typically is defined as the variant of absorptive hypercalciuria that is relatively unresponsive to dietary modifications, including severe dietary calcium restriction, but that normalizes urinary calcium excretion during periods of fasting.
- Type II is the most common variety of absorptive hypercalciuria and usually responds to moderate dietary calcium restriction.
- Type III, also known as renal phosphate leak, is a relatively uncommon cause of hypercalciuria. In this condition, the underlying etiology is a renal defect that causes excessive urinary phosphate excretion. This high urinary phosphate loss rapidly depletes the serum phosphate level, causing hypophosphatemia. This low serum phosphate increases the activation of vitamin D-3, which increases intestinal absorption of both phosphate and calcium. The unnecessary calcium absorbed is ultimately excreted in the urine, causing the hypercalciuria. Essentially, this is an absorptive vitamin D–dependent hypercalciuria due to an inappropriate vitamin D-3 activation from hypophosphatemia. The hypophosphatemia is caused by the renal phosphate–losing defect.
Renal leak hypercalciuria
Renal leak hypercalciuria is due to a specific defect in the kidneys that allows excessive obligatory urinary calcium excretion regardless of serum calcium levels, body stores, or calcium ingestion. The calcium/creatinine ratio usually is high (>0.20). The obligatory loss of serum calcium into the urine produces a mild hypocalcemia and secondary hyperparathyroidism, which is useful in diagnosing this condition. Renal leak hypercalciuria is far less common than absorptive hypercalciuria.
Resorptive hypercalciuria (hyperparathyroidism)
Resorptive hypercalciuria is due to the loss of calcium from the body's normal stores in the bony skeleton and typically is found in hyperparathyroidism. In this condition, calcium is released from bone in response to the increased activity of osteoclasts caused by excessive and inappropriate serum PTH levels. This causes significant hypercalcemia. Under normal conditions, PTH causes the kidney to limit calcium excretion, but, with the overwhelming serum calcium load produced with hyperparathyroidism, the kidneys are forced to excrete the extra calcium into the urine, causing the hypercalciuria.
Table 2. Hypercalciuria Simplified Test Guideline
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Table
| Hypercalciuria Diagnosis | Urinary Calcium on 400-mg Calcium Diet (NL* = <200 mg/24 h) | Fasting Calcium/Creatinine Ratio (NL = <0.11) | Post–Calcium Load Calcium/Creatinine Ratio (NL = <0.20) |
|---|---|---|---|
| NL | NL | NL | NL |
| Absorptive type I | High | NL | High |
| Absorptive type II | NL | NL | High |
| Absorptive type III† | High | High | High |
| Renal calcium leak | High | High | High |
| Resorptive‡ | High | High | High |
| Hypercalciuria Diagnosis | Urinary Calcium on 400-mg Calcium Diet (NL* = <200 mg/24 h) | Fasting Calcium/Creatinine Ratio (NL = <0.11) | Post–Calcium Load Calcium/Creatinine Ratio (NL = <0.20) |
|---|---|---|---|
| NL | NL | NL | NL |
| Absorptive type I | High | NL | High |
| Absorptive type II | NL | NL | High |
| Absorptive type III† | High | High | High |
| Renal calcium leak | High | High | High |
| Resorptive‡ | High | High | High |
*Normal
† Absorptive type III is renal phosphate leak.
‡ Resorptive is hyperparathyroidism.
The Role of Vitamin D
Many cases of absorptive hypercalciuria involve elevated vitamin D levels. Vitamin D increases small bowel absorption of calcium and phosphate, enhances renal filtration, decreases PTH levels, and reduces renal tubular calcium absorption, which ultimately leads to hypercalciuria. An elevated vitamin D level accounts for the finding of fasting hypercalciuria in some cases of absorptive hypercalciuria type I. About 30-40%, and possibly as many as 50%, of patients with absorptive hypercalciuria demonstrate abnormally elevated vitamin D-3 levels compared to the non stone-forming general population.
One suggestion is that some patients have an exaggerated response to, affinity for, or sensitivity to normal levels of vitamin D and its metabolites. Activation of vitamin D-3 takes place in the proximal renal convoluted tubule. This activation can be reduced by ketoconazole therapy. Oral neutral phosphate therapy, limiting vitamin D and calcium intake, and reducing sunlight exposure can also be useful in treating excess vitamin D levels and hypervitaminosis D (usually due to chronic ingestion of excessive vitamin D). Dipyridamole (Persantine) reduces renal phosphate excretion and may also be useful in controlling excessive vitamin D levels and reducing vitamin D–dependent hypercalciuria.
Vitamin D is stored in fat, and, in some cases, the vitamin D intoxication may persist for weeks after vitamin D ingestion has ceased. In these cases, glucocorticoids (roughly 100 mg of hydrocortisone per day or the equivalent) usually return calcium levels to normal within a few days.
Serum vitamin D determinations can be helpful in determining the etiology of hypercalciuria in difficult or resistant cases but probably are unnecessary in most hypercalciuric patients except as part of a research study or other standardized protocol.
Sarcoidosis
Sarcoidosis is a chronic disease that causes granulomas in various parts of the body but most often in the lungs. While the exact cause is unknown, it is thought to arise from an exaggerated cellular immune response. The prevalence in the United States is about 1-4 cases per 10,000 population.
In some sarcoid patients, 1,25-dihydroxyvitamin D is synthesized in an uncontrolled fashion by macrophages in the sarcoid granulomas. This produces a hypervitaminosis D state with hypercalcemia and, frequently, hypercalciuria. Rarely, hypercalciuria is found without the hypercalcemia. This vitamin D overproduction is not controlled by increased serum calcium, PTH, or phosphate administration. Limiting sunlight exposure and reducing vitamin D ingestion are recommended. Glucocorticoid administration usually controls the hypercalcemia and hypercalciuria. Primary hyperparathyroidism has been reported in some patients with sarcoidosis.
Areas of Confusion in Hypercalciuria
Fasting hypercalciuria
Fasting hypercalciuria is the primary characteristic of renal leak and resorptive hypercalciuria. It also is found in renal phosphate leak hypercalciuria and in the vitamin-dependent form of absorptive hypercalciuria type I. Traditional absorptive hypercalciuria type I (not the vitamin D–dependent variant) generally cannot be controlled even with a severely restricted low-calcium diet, but urinary calcium levels normalize during periods of fasting.
Hyperparathyroidism can be differentiated easily by the elevated PTH and hypercalcemia levels found in this condition. Renal leak hypercalciuria has secondary hyperparathyroidism but no hypercalcemia. Renal phosphate leak shows elevated urinary phosphate and reduced serum phosphate, as well as elevated vitamin D blood levels. Ketoconazole, which reduces vitamin D levels, lowers fasting urinary calcium levels in renal phosphate leak and in the vitamin D–dependent form of absorptive hypercalciuria type I. This can be useful in testing questionable cases, but ketoconazole generally is considered too toxic for long-term use in most patients.
Essentially, the variant form of absorptive hypercalciuria type I, which demonstrates fasting hypercalciuria, is a diagnosis of exclusion. If the serum calcium, phosphate, and PTH levels are normal, then the absorptive hypercalciuria type I variant is likely.
Fasting hypercalciuria usually is due to abnormal hormone levels of either vitamin D-3 or PTH. The calcium for the hypercalciuria comes from the skeleton and can cause bone demineralization if left untreated.
Are these different types of hypercalciuria truly separate and distinct entities or are they just the extremes of a single, unified process?
While nobody knows the answer to this question, the evidence and the consensus opinion lean toward the unified theory. In reality, other than for research purposes, this question has little impact clinically because ultimately whatever therapy works is required. The advantage of the calcium-loading test is that physicians can use it to proceed directly to the most effective remedy without the delays and trial and error methodology of the simplified clinical approach. When properly evaluated, 97% of hypercalciuric patients can be classified according to etiology.
How does one differentiate between absorptive hypercalciuria types I and II?
The fasting and post–calcium-loading parameters are essentially the same in these two entities. The main difference is that patients with type I absorptive hypercalciuria still have hypercalciuria, defined as urinary excretion in excess of 200 mg of calcium per 24 hours while on the 400-mg low-calcium diet. Patients with type II absorptive hypercalciuria 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.
How does one differentiate absorptive hypercalciuria from renal leak without a calcium-loading test?
Patients with renal leak hypercalciuria tend to have relatively low serum calciums in relation to their serum 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 they 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 (AMP) levels are often elevated in this condition.
Frequency
United States
More than 30 million Americans experience kidney stone disease, with 1.2 million new cases each year. The percentage of people with hypercalciuria has been estimated to be at least 1 in 3 people who form kidney stones, although some investigators have suggested that hypercalciuria can be found in as many as 60% of all calcium stone formers. It is the most common metabolic abnormality found with calcium nephrolithiasis.
Despite a higher incidence of stone disease in the "stone belt," which primarily is the southeast portion of the United States, no clear biochemical difference was found when risk factors were compared between various other regions of the country. Although nutritional and environmental influences would be expected to produce some variability, stone formers in all of the regions tested showed a striking similarity in urinary chemical risk factor profiles with no significant biochemical differences noted that could be attributable to geographical factors.
International
Overall risk of forming stones differs in various parts of the world. The probability is 1-5% in Asia, 5-9% in Europe, 13% in North America, and 20% in Saudi Arabia. Upper-tract stone disease is associated with an affluent lifestyle in developed countries with diets high in animal protein, while bladder stones are predominant in developing countries and are related to poor socioeconomic conditions.
Mortality/Morbidity
The morbidity of hypercalciuria is related to two separate factors: 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. Pain is unrelated to the size of the stone or its composition and is related only to the rapidity and degree of the obstruction. While 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.
The other problem with hypercalciuria is its possible relationship to osteopenia and osteoporosis, especially when due to resorption (hyperparathyroidism) or renal leak hypercalciuria. In these cases, the extra calcium for the obligatory renal excretion is drawn from the bones and eventually reduces bone density. This can be relieved by surgically or medically correcting the hyperparathyroidism and using thiazides, calcium citrate (instead of other calcium supplements), estrogen (in women), or bisphosphonates (eg, alendronate [Fosamax]). Thiazides can also be helpful in correcting low bone density, even in patients who can normalize their urinary calcium excretion with dietary moderation alone. Studies of calcium stone formers demonstrate that those with hypercalciuria tend to have a lower bone density than non–stone formers and that the bone density is further decreased if patients are on a calcium-restricted diet.
Race
Whites tend to have stones more often than blacks; whether this is due to genetic differences or is secondary to dietary and socioeconomic factors is unclear. The latter is suggested by the increasing incidence of nephrolithiasis in the nonwhite population.
A 1999 study by Whalley and associates from Johannesburg, South Africa, compared lithogenic risk factors in healthy male black volunteers, male black stone formers, and white males who are recurrent stone formers. The subjects were observed over a 10-year period and were assessed with a thorough history, dietary analysis, and serum and urinary chemistry evaluation. The researchers concluded that black male stone formers had similar chemistry profiles to those of the white male stone formers, although the risk factors were generally less severe. No significant family history of stone disease was present in the black population studied, which suggests that genetic factors may be of more importance in the etiology of stone formation among whites. Although the study had a relatively small number of black subjects, it still suggested some important differences in the etiology of stone disease between blacks and whites that need to be confirmed by other investigators.
Similar findings were reported by Maloney and associates, who found that all racial groups tested (white, black, Asian, Hispanic) demonstrated remarkable similarity in the incidence of underlying metabolic abnormalities.
A more recent study by Rodgers and Lewandowski evaluated the effect of various standardized diets on urinary stone risk factors between a group of blacks compared with a matched group of whites. The groups were not known stone formers. The researchers found that a low-calcium diet caused a statistically significant increase in urinary oxalate in black subjects but not in white subjects. The high-oxalate diet also showed differences between the black and white groups.
Sex
The reference range of urinary calcium excretion for men generally is 275 mg or less per day, while in women the usual daily limit is only 250 mg. These reference values were created using large numbers of people (not calcium kidney stone formers) to establish a reference range. The most likely reason for the discrepancy is that men generally are larger physically than women and have a correspondingly larger amount of material, such as calcium and uric acid, to excrete. Clearly, stone development occurs when the chemical conditions are favorable, regardless of what any arbitrary reference range might be. For most practical purposes, the 250-mg/day limit for 24-hour urinary calcium excretion or a concentration of no more than 200 mg of calcium/liter of urine is used regardless of sex when the relative severity of hypercalciuria and overall risk of calcium kidney stone production are considered.
Postmenopausal women are more likely than men to demonstrate hypercalciuria. Hyperparathyroidism, which produces hypercalciuria, is more common in older women. Calcium supplementation also is more popular with women because of their concerns about possible osteoporosis.
A study involving only women demonstrated that women who develop calcium kidney stones had an average calcium intake that was 250 mg/day less than that of non–stone forming women. This finding agrees with other studies that suggest that calcium stone formers should not restrict their calcium intake too aggressively.
Urinary chemistry and stone formation rate data were analyzed with the demographic information from a large national database of kidney stone formers. Researchers specifically compared new stone formation rates with body weight for men and women and found that obesity is a risk factor for kidney stone disease in women but not in men. This finding is similar to that found in 2 large studies involving 81,000 women in the Nurses' Health Study compared with 51,000 men in the Health Professionals Followup Study. Investigators at Harvard who conducted these 2 studies found that body size was a positive risk factor for kidney stone disease in women, but the correlation was much less significant in men. The reason for this is unclear, but it may be related to estrogen levels. Whether this increased risk in women disappears when the excess body weight is lost also is unclear.
High-dose vitamin B-6 appears to be beneficial in women with calcium oxalate stone disease but probably not in men. Using data from more than 85,000 women with no history of kidney stones whose cases were monitored for 14 years, investigators found that those who took large amounts of vitamin B-6 had a significantly lower incidence of new calcium oxalate stone formation. A similar benefit of reduced calcium stone production from increased vitamin B-6 intake was not evident in an equivalent male study group. Similarly, carbohydrate intake was found to be a kidney stone dietary risk factor for women but not for men. (Incidentally, these studies found no benefit to dietary vitamin C modifications in either men or women.)
A study of healthy postmenopausal women (not calcium stone formers) showed that those administered calcium supplements alone did not demonstrate any significant increase in their urinary calcium excretion while those administered calcium and calcitriol did have a significant increase in their urinary calciums. This did not result in any increase in overall stone risk or calcium oxalate activity product due in part to a simultaneous decrease of about 20% in urinary oxalate levels. These findings suggest that calcium supplementation, with or without calcitriol, does not increase the risk of calcium urolithiasis significantly in healthy (non–stone-forming) postmenopausal women even though they may increase their urinary calcium excretion. Theoretically, a thiazide diuretic would reduce the urinary excretion of calcium and could be of some therapeutic benefit for this group at risk for osteoporosis.
Pregnancy has long been thought to increase the incidence of urinary stones and hypercalciuria. Healthy, non–stone-producing pregnant women have been found to have hypercalciuria during all 3 trimesters. In addition, urinary oxalate, magnesium, and citrate levels were also increased during pregnancy. This suggests that the overall risk of nephrolithiasis during pregnancy may not be increased substantially since urinary stone promotors and inhibitors were both increased.
Finally, female sex hormones may play a somewhat protective role in overall kidney stone formation. The rough male-to-female ratio of stone production of 3:1 does not apply to children or to women who are postmenopausal, which supports the hypothesis that female sex hormones play some beneficial role. Researchers have studied the effects of female sex hormones in a rat model in which stone formation was induced by ethylene glycol and vitamin D supplementation (Iguchi, 1999). The study suggested that female sex hormones were protective by reducing the likelihood of stone formation through decreasing urinary oxalate, osteopontin, and renal calcium levels.
Age
The peak age range for calcium kidney stone production generally is 35-45 years. Another peak incidence of hypercalciuria occurs in some postmenopausal women. In this older age group, many are taking supplemental calcium for osteoporosis prophylaxis or therapy. The excess absorbed calcium eventually is released into the urine. In addition, postmenopausal women are at an increased risk of hyperparathyroidism, which can cause hypercalciuria.
Geriatric stone disease is relatively uncommon. The risk for newly formed stones in patients older than 65 years is quite low, although once a stone has formed the number and type of risk factors, as well as the risk of recurrent stones, is similar to younger stone formers. The incidence of hyperparathyroidism in particular is higher in older persons and should be considered whenever an older patient presents with a first calcium kidney stone, particularly if the patient is female. (See Management of hypercalciuria in osteoporosis for more details about treatment of hypercalciuria in postmenopausal women with osteoporosis or osteopenia.)
In children, hypercalciuria often is associated with some degree of hematuria, back or abdominal pain, and, sometimes, 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 often are lost to follow-up. One recent study looked at the long term effects of hypercalciuria in children and several possible therapies over a 4- to 11-year period. The conclusion was that, regardless of treatment, most children with hypercalciuria eventually become asymptomatic while remaining hypercalciuric. 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.
Another study involving children looked at recurrent abdominal and flank pain associated with hypercalciuria. One hundred and twenty-four children with hypercalciuria were studied. A family history of kidney stone disease was present in 50% of these children. 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 responded to therapy. Resolution of the hypercalciuria eliminated the recurrent pain in this patient population.
Clinical
History
In 1939, urologist Ruben Flocks first recognized hypercalciuria as a clinically significant entity associated with renal stone disease. The definition of hypercalciuria has changed only slightly since then. Usually, normal laboratory values are determined by sampling a large healthy population and establishing a reference range, usually of 2-3 standard deviations. This methodology may establish what is common in the population but may fall be inadequate when looking at a select group, such as calcium stone formers. In this group, merely maintaining the urinary calcium within the reference range levels may still leave sufficient chemically active calcium to form stones due to the influence of other stone-promoting chemical risk factors. The methodology also does not consider urinary calcium concentration or the overall activity of the other urinary stone promotors and inhibitors.
Optimal levels of urinary calcium have not been determined, although less than 125 mg of calcium per liter of urine has been suggested as a reasonable optimal goal for most calcium stone formers. Several commercial medical reference laboratories calculate specific supersaturation ratios for calcium oxalate and calcium phosphate. These calculations are based on the EQUIL2 computer program developed by the late urologist Birdwell Finlayson, MD, and are the basis for all of the commercially available stone prevention programs. (See Nephrolithiasis: Laboratory Evaluation of Stone Formers for more information on specific laboratories and their programs.)
Causes
Hypercalciuria can be caused by various mechanisms. The most clinically relevant of these mechanisms or etiologies, the methodologies for their differentiation, and criteria for treatment selection are discussed in this article.
Hypercalciuria can be viewed several ways. In the traditional approach, an effort is made to formally study the exact cause of the hypercalciuria, ultimately establishing a more precise diagnosis, which leads 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. Both methods of diagnosis and classification are reviewed in the following sections.
Traditional approach overview
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, which 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 it 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.
Simplified clinical approach overview
An alternate approach to hypercalciuria is based on the clinical response of the patients. 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 (see Traditional approach to hypercalciuria—the calcium-loading test), to determine the exact etiology of the excess urinary calcium. Instead, a therapeutic trial of therapy is instituted, usually based on dietary guidelines.
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 isrepeated 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.
More on Hypercalciuria |
 Overview: Hypercalciuria |
| Differential Diagnoses & Workup: Hypercalciuria |
| Treatment & Medication: Hypercalciuria |
| Follow-up: Hypercalciuria |
| Multimedia: Hypercalciuria |
| References |
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References
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Further Reading
Keywords
absorptive hypercalciuria, calcium-loading test, calcium stone disease, calcium stones, Dent disease, elevated urinary calcium, high urinary calcium, hyperparathyroidism, geriatric hypercalciuria, idiopathic hypercalciuria, ketogenic diet, medullary sponge kidney, MSK, nephrolithiasis, osteoporosis, pediatric hypercalciuria, renal calculi, renal leak hypercalciuria, renal phosphate leak, resorptive hypercalciuria, sarcoid, urolithiasis
