Hypercalciuria, or excessive urinary calcium excretion, occurs in about 5-10% of the population[1] and is the most common identifiable cause of calcium kidney stone disease. (The other significant causes include hyperoxaluria, hyperuricosuria, low urinary volume, and hypocitraturia.)
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.
Definitions
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 can also 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 of hypercalciuria 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 milliequivalent [mEq] sodium) diet.
Table 1 below, outlines the various definitions of hypercalciuria based on a regular or restricted diet.
Table 1. Definitions of Hypercalciuria
View Table
See Table
Limitations of hypercalciuria definitions
Several experts, including the author of this article and Dr. Gary Curhan of Harvard University, 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.[2] 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. Although 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.[2] 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.
Clinically significant hypercalciuria
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. Recent evidence suggests that this classical differentiation is insufficient to explain all of the cellular and genetic variations that have been noted.[1]
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, among others.
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.
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.
Dietary calcium
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/d in a healthy population but raises urinary calcium levels by 20 mg/d in hypercalciuric patients.
Animal protein, sodium, alcohol, caffeine, and other dietary factors
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/d.
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.
Absorptive hypercalciuria, renal leak hypercalciuria, and resorptive hypercalciuria (hyperparathyroidism) are discussed in this section.
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.[3]
Increased intestinal calcium absorption produces a corresponding increase in serum calcium levels. Typically, serum parathyroid hormone (PTH) is low or in the low-normal range in absorptive hypercalciuria, because the serum calcium level is generally high. Mild or moderate absorptive hypercalciuria can usually be controlled solely with dietary measures, 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.[4] This mouse model is similar to Dent disease in humans, which is a rare X-linked heritable disorder with reduced CLC5 activity that is 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 with the healthy controls.[4] 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.[4] 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 is typically 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. The 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 is usually 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 is typically 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.
Below, Table 2 provides simple test guidelines for specific diagnoses of hypercalcinuria.
Many cases of absorptive hypercalciuria involve elevated vitamin D levels.[3] Vitamin D increases small bowel absorption of calcium and phosphate, enhances renal filtration, decreases parathyroid hormone (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 with 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 these tests are probably are unnecessary in most hypercalciuric patients except as part of a research study or other standardized protocol.
Sarcoidosis and hypervitaminosis D
Sarcoidosis is a chronic disease that causes granulomas in various parts of the body but most often occurs in the lungs. Although the exact cause is unknown, this condition 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.[5]
Fasting hypercalciuria; whether the different types of hypercalciuria are truly separate and distinct entities or the extremes of a single, unified process; differentiating between absorptive hypercalciuria types I and II; and differentiating absorptive hypercalciuria from renal leak without a calcium-loading test are discussed in this section.
Fasting hypercalciuria
Fasting hypercalciuria is the primary characteristic of renal leak and resorptive hypercalciuria. It is also 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 parathyroid hormone (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 is generally 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 is usually 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?
Although the answer to this question is not currently known, 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 2 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 calcium levels 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 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 (AMP) levels are often elevated in this condition.
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 is primarily 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 geographic factors.
Globally, the overall risk of forming stones differs in various regions. 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, whereas bladder stones are predominant in developing countries and are related to poor socioeconomic conditions.
Mortality and morbidity
The morbidity of hypercalciuria is related to 2 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. 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.
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.
Racial differences
White persons tend to have stones more often than black individuals; 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 study by Whalley and associates from Johannesburg, South Africa, found 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.[6] The investigators 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. 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.[6]
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.[6] 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.[7]
A study by Rodgers and Lewandowski found that a low-calcium diet caused a statistically significant increase in urinary oxalate in black subjects but not in white subjects.[8] A high-oxalate diet also showed differences between the black and white groups. The investigators evaluated the effect of various standardized diets on urinary stone risk factors between a group of black persons compared with a matched group of white persons. The groups were not known stone formers.[8]
Sex differences
The reference range of urinary calcium excretion for men generally is 275 mg or less per day, whereas 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 are generally 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/d 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 (see Table 1 under Overview of Hypercalciuria).
Postmenopausal women are more likely than men to demonstrate hypercalciuria. Hyperparathyroidism, which produces hypercalciuria, is more common in older women. Calcium supplementation is also 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/d 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; the 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 Follow-up 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.[2] The reason for this finding is unclear, but it may be related to estrogen levels. Whether this increased risk in women disappears when the excess body weight is lost is also 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, whereas those administered calcium and calcitriol did have a significant increase in their urinary calciums. However, 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.[9] 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, as 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. In a rat model in which stone formation was induced by ethylene glycol and vitamin D supplementation, the results suggested that female sex hormones were protective by reducing the likelihood of stone formation through decreasing urinary oxalate, osteopontin, and renal calcium levels.[10]
Age distribution
The peak age range for calcium kidney stone production is generally 35-45 years. Another peak incidence of hypercalciuria occurs in some postmenopausal women. In this older age group, many women 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. In particular, the incidence of hyperparathyroidism 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.
In children, hypercalciuria is often 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 are often lost to follow-up. One study that looked 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.[11] 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 124 children looked at recurrent abdominal and flank pain associated with hypercalciuria.[12] 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.[12]
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.
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 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.
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 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 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.
Differentials
The following conditions are included in the differential diagnosis:
Hypercalcemia
Hypercalcemic nephropathy
Hyperoxaluria
Hyperparathyroidism
Hypervitaminosis D
Hypophosphatemia
Nephrocalcinosis
Nephrolithiasis
Nephrolithiasis: Acute Renal Colic
Osteoporosis
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, among others.
Evaluation of Hypercalciuria
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 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.)
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; 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. Other 24-hour urine chemistries that are usually performed in stone formers (in addition to calcium) include the following: oxalate, pH, volume, creatinine, specific gravity, phosphorus or phosphate, citrate, sodium, uric acid, magnesium, and either urea nitrogen or sulfate (which are increased in cases of high protein ingestion). If possible, these chemistries should all be performed together.
Ensure that the laboratory performing the studies has a reliable methodology for urinary chemistry testing. In the United States, this usually 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. (Patients who are more intelligent are often the ones who rush through the instructions and misunderstand, delivering grossly inaccurate specimens.) One easy way to determine the urine collection accuracy 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 those predicted probably represent improper or inaccurate collections.
Ideally, serum laboratory studies should be drawn at the same time 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 serum calcium, phosphorus, electrolytes, uric acid, and creatinine. High serum calcium levels should be repeated, along with parathyroid hormone (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.)
Two distinct approaches to the laboratory evaluation of hypercalciuric patients exist. With both, initial blood testing, such as serum calcium, creatinine, and phosphate, 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.
In the traditional approach, a calcium-loading test is performed. This is based on the principle that, during a defined period of fasting, patients with absorptive hypercalciuria show a significant decrease in urinary calcium excretion. Patients with renal leak hypercalciuria, in which the kidney has an obligatory calcium-losing defect, are expected to show relatively little effect from dietary measures alone, including fasting. Patients are then administered a large oral calcium meal, and urine samples are obtained periodically afterwards. Patients with absorptive hypercalciuria tend to greatly increase their urinary calcium excretion after a large calcium meal, whereas patients with renal leak hypercalciuria do not demonstrate as large an increase. In practice, performing the calcium-loading test is difficult, tedious, and usually reserved for selected cases in a tertiary care center or for research purposes.
The simplified clinical approach is becoming increasingly popular. It involves an attempt to use dietary measures alone (diet test) to control urinary calcium excretion (after first screening the patient with blood tests for kidney failure, hyperuricemia, hypophosphatemia, and hypercalcemia.) If successful, no further treatment is necessary other than routine monitoring. If unsuccessful, the patient requires medical therapy.
Not only is the simplified clinical approach much easier to perform and follow, but 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.
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 collected and analyzed for calcium while the patient is on a regular diet. This is undertaken to confirm the diagnosis, establish the baseline urinary calcium level, and to 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 an additional 400-600 cc of water to drink. For the next 2 hours, the patient continues fasting but does not urinate again until 9 am, when he or 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 both 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.
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.
Interpreting the calcium-loading test
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 type I absorptive hypercalciuria typically do not normalize their urinary calciums 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.
Patients with renal leak hypercalciuria and hyperparathyroid (resorptive) hypercalciuria are hypercalciuric regardless of oral calcium intake, so they show more than 200 mg of urinary calcium excretion per 24 hours on the calcium-restricted diet and high calcium/creatinine ratios in both phases of the calcium-loading test. Serum calcium level differentiates between these 2 diagnoses, because renal leak hypercalciuria has low serum calcium levels, whereas hyperparathyroid patients are hypercalcemic.
Below, Table 3 provides a summary of how to interpret the results of the calcium-loading test.
Table 3. Calcium-Loading Test Interpretation Guide
Virtually all patients can be treated quite successfully using a simplified approach to hypercalciuria without the need for a formal calcium-loading test.
After initial history and laboratory testing, including serum and 24-hour urinary chemistries as outlined previously, hypercalciuric patients undergo a short-term trial of dietary modification. Patients with hypercalcemia and elevated parathyroid hormone (PTH) levels probably have hyperparathyroidism and should be treated appropriately.
The test diet includes a moderate dietary calcium intake of about 600-800 mg/d. 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 diminished 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, then they can be treated successfully with this method. If they still have significant hypercalciuria, patients need medical therapy such as 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.
Advantage of the simplified clinical laboratory approach to hypercalciuria
The advantage of the simplified approach is obvious. Only a short-term trial of dietary therapy is needed to determine if 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 to hypercalciuria
The summary is as follows:
Complete a medical history with 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 type III hypercalciuria. Verify the diagnosis with a vitamin D-3 level or a clinical trial of orthophosphate therapy.
Start a therapeutic trial of dietary modification treatment.
Repeat the blood and 24-hour urine testing.
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, bisphosphonates, or sodium cellulose phosphate can be used if thiazides are not tolerated well or fail to control urinary calcium levels adequately. Patient whose hypercalciuria fails all of these therapies require further evaluation.
Medullary sponge kidney is a congenital condition that can be diagnosed only by intravenous pyelogram (IVP). This 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.
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 number is not known for certain, it ranges from 2.6% to 21% in various studies.) No specific treatment exists, but 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 more prominent in the proximal urinary tract epithelial cells. Deeper structures showed increased mitotic activity, edema, vasodilatation, and separation of collagen fibers.
In the kidney, findings include interstitial edema, vasodilatation, tubular degeneration, and vacuolization of both the proximal and distal convoluted tubules.
Dietary modifications have long been the mainstay of initial therapy for hypercalciuria. Although dietary changes alone may not always be successful or adequate, dietary excesses possibly can undermine or defeat even optimal medical treatments. Patients who normalize their urinary calcium excretion with dietary changes alone may still benefit from thiazides or other treatments to avoid or treat bone demineralization and osteoporosis or osteopenia.[13] Reducing intestinal calcium inadvertently may increase oxalate absorption and contribute to hyperoxaluria, resulting in a net increase in stone formation risk rather than a reduction. This is why dietary oxalate is limited whenever calcium intake is reduced.
All hypercalciuric patients are advised to follow reasonable dietary changes to help limit their urinary calcium loss, reduce stone recurrences, and improve the effectiveness of medical therapy.
Dietary treatment guidelines
The following are recommendations in the dietary treatment of hypercalciuria:
Limit daily calcium intake to 600-800 mg/d unless otherwise instructed.
Limit dietary oxalate, especially when calcium intake is reduced. High oxalate levels are found in strong teas, nuts, chocolate, coffee, colas, green leafy vegetables (eg, spinach), and other plant and vegetable products.
Avoid excessive purines and animal protein (< 1.7 g/kg of body weight).
Reduce sodium (salt) and refined sugar to the minimum possible.
Increase dietary fiber (12-24 g/d).
Limit alcohol and caffeine intake.
Increase fluid intake, especially water (sufficient to produce at least 2 L of urine per day).
Dietary modifications involving reasonable restrictions of dietary calcium, oxalate, meat (purines) and sodium, have been useful in reducing the urinary supersaturation of calcium oxalate. This effect is more pronounced in hypercalciuric calcium oxalate stone formers than in calcium nephrolithiasis patients who are normocalciuric. Urinary calcium was found to decrease by 29% when reasonable dietary changes alone were used in a study by Pak and associates.[14]
Some have suggested that the following 3 criteria need to be fulfilled for any dietary factor to be implicated in kidney stone disease:
Intake of the dietary constituent should be increased in patients with stones compared with controls.
Restriction of the dietary factor should decrease stone formation rates.
The reason the dietary factor causes stones needs to be understood.
The main dietary contributions of calcium, sodium, potassium, animal protein, fiber, alcohol, caffeine, fluid intake, oxalate, and carbohydrates are reviewed individually below. No relationship was found with dietary fat intake.
Calcium intake
Avoidance of an excessively high-calcium diet is an obvious recommendation for calcium stone formers. (See the image below for a list of calcium rich foods.) Stone formers as a group are much more sensitive to dietary calcium than non–stone formers. For any given change in dietary calcium, urinary calcium has been shown to increase an average of only 6% in healthy controls, but this can increase 20% in calcium stone formers.
View Image
Calcium-rich foods.
Avoiding a diet that is too severely limited in calcium is also important, because of the risk of a reactive hyperoxaluria and the creation of a negative calcium balance with subsequent osteopenia or actual osteoporosis. In 2 large population studies involving both men and women, patients with the highest daily calcium intake were demonstrated to have significantly fewer stones (within reasonable limits) than those with the lowest dietary calcium levels.
Any patient with kidney stones placed on a long-term, reduced calcium diet for any reason should have their bone density measured periodically, preferably in the spine. Urinary oxalate levels should also be checked regularly because of the risk of hyperoxaluria.
The recommended dietary calcium intake for most calcium stone formers is about 600-800 mg/d. When calcium is removed from the diet without also restricting oxalate intake, the lack of intestinal oxalate-binding sites will possibly leave too much intestinal oxalate unbound and available for easy absorption. When this occurs, urinary oxalate levels rise. Proportionately, oxalate is 15 times stronger than calcium in promoting nephrolithiasis. The net stone formation rate may actually increase if dietary oxalate intake and hyperoxaluria are not controlled.
Calcium citrate is recommended if calcium supplements are needed. This combination has been shown to be the most effective in limiting the new stone formation rate for those who require calcium supplements.
Sodium intake
A high sodium intake promotes various effects that enhance urinary calcium excretion and increase overall kidney stone formation rates. These effects include a rise in urinary pH, higher urinary calcium and cystine levels, and a decrease in urinary citrate excretion. In healthy adults, a high sodium intake has been associated with higher fractional intestinal calcium absorption as well as increased parathyroid hormone (PTH) and vitamin D-3 levels. As mentioned earlier, each 100-mEq increase in daily dietary sodium raises the urinary calcium level by about 50 mg.
Increased calcium excretion is thought to be due to an increase in the extracellular fluid volume, which ultimately results in an inhibition of calcium reabsorption in the distal renal tubule. Reducing dietary sodium has been shown to decrease urinary calcium excretion in hypercalciuric stone formers, whereas high dietary sodium is associated with both increased urinary calcium excretion and low bone density.
The rise in urinary pH is caused by an increase in serum and urinary bicarbonate levels. High serum bicarbonate lowers urinary citrate excretion by a direct effect on citrate metabolism in proximal renal tubular cells.
Sodium intake among stone formers is equal to or higher than the intake in control groups of non–stone formers. Enhanced renal calcium excretion from high dietary sodium is thought to be due to an increase in the extracellular fluid volume, which ultimately results in an inhibition of renal tubular calcium reabsorption. Sodium and calcium share common sites for reabsorption in the renal tubules. Patients with recurrent nephrolithiasis and hypercalciuria are also the most sensitive to the hypercalciuric actions of a high-sodium diet. Finally, in postmenopausal women, high sodium intake has been directly associated with low bone density in calcium stone formers.
Dietary sodium needs to be controlled during any calcium testing, such as a calcium-loading test, to avoid affecting the results.
Most experts recommend limiting dietary sodium (salt) in calcium stone formers to about 100 mEq/d, but this is difficult because salt (sodium) enhances the taste of food to many people. Patients should be aware that most restaurant meals and fast food items, such as pizza, contain a considerable amount of sodium. Many prepared foods have low-sodium varieties available. Ketchup, mustard, teriyaki, Worcestershire and soy sauces, canned soups, cold cuts, prepared vegetables, and TV dinners all have large amounts of sodium. Daily dietary salt intake should be restricted to levels sufficient to keep the urinary sodium excretion below 150-200 mEq/d.
Recommendations to reduce sodium (salt) intake include the following:
Remove the saltshaker from the dining table. Other spices, such as pepper, salt substitutes, or Mrs. Dash, can be used instead.
Use little or no salt in food preparation or cooking.
Avoid eating foods with high salt content whenever possible. Most fast food is high in sodium.
Do not add any additional salt to foods that already contain it. This would apply to most prepared or canned foods, such as soups, gravies, TV dinners, and canned vegetables.
Use fresh or frozen vegetables whenever possible. To reduce the salt content of canned vegetables, they should be drained and then rinsed with water before cooking.
Use one half or less of the specified amount of salt when following cooking recipes.
Everyone in the family should participate in the low-sodium diet so the patient does not feel singled out.
Potassium intake
Some evidence suggests that low potassium intake may be a risk factor for stones, but this has not been confirmed in all studies.[15, 16, 17] The potential influence of a low-potassium diet may be due to its relationship to sodium intake in stone formers, who generally have a higher sodium/potassium ratio than non–stone formers.
Potassium decreases urinary calcium excretion due to an induced transient sodium diuresis resulting in a temporary contraction of the extracellular fluid volume and an increase in renal tubular calcium reabsorption. Potassium also increases renal phosphate absorption, raising serum phosphate levels, which reduces serum vitamin D-3, resulting in decreased intestinal calcium absorption.
Animal protein intake
The possible link between high animal protein intake and kidney stones has been known since at least 1973. This link has been found in epidemiologic studies first in India, then in England, Germany, Austria, Japan, Italy, and, finally, in the United States. A large prospective study in the United States found a significantly increased risk of stones in the group with the highest animal protein intake.[18] Additionally, known stone formers appear to be more sensitive to the stone-enhancing effects of high–animal protein diets than non–stone forming control populations.
Animal protein affects urinary calcium mainly through its acid-loading ability. Animal protein is high in purines, which are metabolized to uric acid, further contributing to the acid load. Animal protein also increases the body's acid load directly. Methionine and cystine are more common in animal protein than plant protein. Both methionine and cystine contain relatively high levels of sulfur. When the sulfur is oxidized to sulfate, additional acid is generated. Sulfate also can form a soluble complex with calcium in the renal tubules, which can reduce calcium reabsorption and contribute to hypercalciuria. Urinary sulfate levels can be used as a general marker of oral animal protein intake. Normal levels generally are 40 mg/d or less, whereas optimal levels in calcium stone formers would be below 25-30 mg daily.
The increased acid needs to be neutralized. This often occurs in the bone, where the extra acid is buffered, releasing calcium from the bony stores. The released calcium eventually contributes to increased urinary calcium. Acid loading directly inhibits calcium reabsorption in the distal renal tubule, which further exacerbates any hypercalciuria. The extra acid also reduces urinary citrate excretion by enhancing citrate reabsorption in the proximal renal tubule.
Each 75 g of additional dietary animal protein raises the urinary calcium level by 100 mg/d. In one study, increasing methionine ingestion by just 6 g/d was found to raise the daily urinary calcium excretion by 80 mg. Dietary animal protein intake should be less than 1.7 g/kg of body weight per day.
High protein intake has been judged second only to vitamin D ingestion in its ability to increase intestinal calcium absorption. Other effects of a high animal protein diet include increased urinary oxalate and uric acid, as well as reduced urinary citrate.
An intriguing randomized study compared the stone production rates in about 100 known calcium oxalate stone formers who differed in their dietary protein and fiber intakes and found significantly fewer stones in the group with the high-fiber, low–animal protein diet.[19] Of course, the possibility exists that the fiber or just the combination of the high fiber and animal protein restriction was effective. The first group was instructed just to increase fluid intake, whereas the second group was told to increase fluid intake and consume a high-fiber, low–animal protein diet; both groups were observed for 4.5 years.[19] Additional studies are needed to determine exactly which dietary modifications are most efficacious and to eliminate the variables, such as uncontrolled sodium and calcium intake, which might influence the outcome.
Finally, a link between high animal protein ingestion and increased oxalate excretion may exist. For example, glycolate is an oxalate precursor whose generation is highly linked to animal protein intake. Although some investigators have found a link between high animal protein intake and increased urinary oxalate, others have not. Further studies are needed to determine the presence and significance of any such correlation.
Fiber intake
Calcium stone formers as a group have a lower intake of dietary fiber than healthy control populations. Dietary fiber, including oat, wheat, and rice bran, can reduce hypercalciuria and lower intestinal calcium absorption by 20-33%. As much as 24 g of dietary fiber per day may be necessary. Wheat bran, for example, is rich in oxalate, which accounts in part for its ability to bind and absorb free intestinal calcium. Although no reports of significant problems with increased dietary fiber have been made, some potential risks exist.
Dietary fiber may reduce intestinal magnesium, resulting in a deficit. Patients on a very high-fiber diet should be checked periodically for magnesium deficiency. A magnesium supplement, such as magnesium oxide, can be added if necessary.
Another potential problem is a reactive enteric hyperoxaluria. Whenever intestinal calcium is reduced, fewer intestinal oxalate-binding sites are available. This leads to more free intestinal oxalate, which is absorbed easier than oxalate bound to calcium or other agents. The increased free intestinal oxalate is absorbed and is eventually excreted in the urine, increasing urinary oxalate levels.
Because oxalate is proportionately about 15 times stronger than calcium with regard to stone promotion, limiting oxalate absorption in known stone formers makes sense. The easiest way to accomplish this is to limit dietary oxalate any time intestinal oxalate-binding sites (such as dietary calcium intake) are reduced. Dietary oxalate can be lowered by limiting such foods as iced tea, coffee, colas, green leafy vegetables, collard greens, spinach, chocolate, nuts, and rhubarb. Another approach is to use an alternate oxalate-binding agent, such as iron supplements.
Alcohol intake
Acute alcohol ingestion causes hypoparathyroidism with hypercalciuria and hypocalcemia. PTH levels can drop by 70% after acute alcohol intoxication. Prolonged but moderate alcohol intake eventually raises PTH levels. People with chronic alcoholism develop low serum vitamin D levels, which cause impaired intestinal calcium absorption and hypocalciuria. A direct inhibitory effect on osteoblast activity by alcohol ingestion also appears to exist. This effect is enhanced in smokers. Urinary calcium excretion during periods of alcohol consumption can increase by over 200% over control subjects. Osteopenia has also been linked to alcohol consumption.
Caffeine intake
Caffeine has been shown to increase urinary calcium excretion, but the clinical importance is relatively small unless very large amounts of caffeine are ingested. As noted in Overview of Dietary Factors, ingestion of 34 ounces of caffeine is necessary to cause the loss of 1.6 mmol of total calcium. This caffeine-induced hypercalciuria seems to parallel changes in urinary prostaglandin F2-alpha (PGF2-alpha), which suggests that prostaglandins may play a role in this entity.
Fluid intake
Several studies have shown that, on average, stone formers have a lower overall fluid intake than non-stone formers. Not surprisingly, the highest incidence of kidney stone formation was in the group with the lowest overall fluid intake.
The need for a high fluid intake to increase urinary fluid volume seems obvious, because extra water decreases urinary concentration and reduces the likelihood of stones even if the total calcium excretion is unchanged. The amount of extra water to be consumed is variable. In general, the author suggests an amount of water that produces a 24-hour urinary volume of 2000 mL or more. This amount may need to be increased in selected cases.
Citrus intake
Potassium-rich citrus fruits and juices, such as oranges, grapefruit, and cranberries, are recommended. Orange juice, for example, has natural potassium citrate. Lemon juice also has a very high citrate content, so lemonade made from real lemon juice is recommended. In contrast, lime juice contains mostly citric acid and does not increase urinary citrate substantially.
Oxalate intake
Oxalate is an organic acid found primarily in the leaves, bark, and fruit of plants. Its only known function in plants is to bind tightly with calcium. This is useful because it allows the plant to extract unwanted calcium from the internal circulation. The leaves containing the calcium-oxalate complex then can be discarded or shed by the plant. Humans absorb oxalate when the oxalate-containing leaves and other vegetable products are eaten. Oxalate has no known useful function in human nutrition.
A relatively mild restriction of foods that contain high amounts of oxalate enables the body to avoid a reactive hyperoxaluria when intestinal oxalate-binding sites are reduced from a drop in oral calcium intake. Common foods with relatively high oxalate content include nuts, chocolate, colas, green leafy vegetables, rhubarb, spinach, collard greens, and tea.
Refined carbohydrate intake
Several large population studies have investigated the issue of the potential contribution of a high-carbohydrate diet to stone production. For example, Curhan found that carbohydrates were not a significant risk factor for stone formation in men, but they were associated with an increased stone production in women. Some investigators have found that stone formers tend to have a higher carbohydrate intake than non-stone formers, but other researchers have failed to confirm such an association.
Good evidence indicates that a high-carbohydrate diet causes an increase in urinary calcium excretion because of decreased distal renal tubular calcium reabsorption and an increase in intestinal calcium absorption. There is also evidence to indicate that excessive carbohydrate loading can increase endogenous oxalate production. This seems reasonable, because glucose is involved in oxalate metabolism through a series of chemical interactions with glyoxylate. (Glyoxylate is involved not only in the metabolism of endogenous oxalate but also in the gluconeogenesis pathway and urea metabolism.)
Ketogenic diet
The ketogenic diet is sometimes used to treat intractable seizure disorders in children. It involves an initial period of fluid restriction and starvation until ketone bodies appear in the urine. This is followed by a low-protein, low-carbohydrate, and fluid-restricted diet, which tends to cause chronic metabolic acidosis with hypocitraturia and relatively low urinary volumes, which, in turn, induce kidney stone formation. Elevated uric acid levels have also been reported.
The average time from initiation of the diet until stone presentation is about 18 months, so patients who are started on this diet should be checked for stone formation at about 12 months after diet application. Fluid liberalization and citrate supplements can be used to prevent kidney stone formation in these patients.
Medical therapy of hypercalciuria is used whenever dietary treatment guidelines alone are inadequate, ineffective, unsustainable, or intolerable for the patient. Generally, medical therapy should be used together with dietary treatment guidelines for optimal results and health.
Medications used in the treatment of hypercalciuria include diuretics (thiazides, indapamide, amiloride), orthophosphates (neutral phosphate), bisphosphonates (alendronate), and, rarely, calcium-binding agents (sodium cellulose phosphate). Occasionally, ketoconazole and dipyridamole are useful in lowering vitamin D levels in selected cases. These therapies should be used together with dietary treatment guidelines. Combination therapy with multiple medicines is possible and recommended in unusual or difficult cases.[20]
Thiazides
Thiazides are currently the mainstay of medical therapy for hypercalciuria. These agents specifically stimulate calcium reabsorption in the distal renal tubule and can reduce urinary calcium excretion by about 30% in hypercalciuric patients. This hypocalciuric effect is reduced if sodium intake is not limited. Yendt et al first described the use of thiazides in nephrolithiasis in 1966, and these agents have been used extensively for kidney stone prophylaxis and as hypercalciuria therapy since then.[21]
Thiazides are specifically indicated for renal leak hypercalciuria, in which case they not only reduce the inappropriate renal calcium loss but also lower parathyroid hormone (PTH) levels and correct other metabolic problems. When used appropriately in renal leak hypercalciuria, thiazides prevent secondary hyperparathyroidism and normalize vitamin D-3 synthesis, calcium absorption, and urinary calcium excretion. Stone formation rates drop more than 90% in patients with renal calcium leak who are placed on long-term thiazide therapy.
When used for absorptive hypercalciuria, thiazides are still effective in reducing hypercalciuria, but their long-term usefulness may diminish over time as the bone stores become filled, allowing the hypercalciuria to return. Until then, bone density on thiazide therapy has been shown to increase by about 1.5% or more per year. When thiazides lose their hypocalciuric effect, which has been reported to occur at an average of about 2 years after initiating therapy, the use of an alternate regimen for a period of approximately 6 months usually restores the efficacy of the thiazide medication for use in hypercalciuria.
Thiazides do not directly affect intestinal calcium absorption. In addition to their effect on the distal renal tubule, these agents decrease the extracellular fluid volume and increase proximal renal tubular calcium reabsorption. Thiazides generally lower urinary calcium levels by about one third, but reductions of as much as 50% or 400 mg of calcium per day are possible and have been reported.
Even when used in a nonselective fashion, thiazides can reduce stone recurrences from 50% (untreated) to 20% (treated) over 5 years. Thiazides are particularly well suited for hypercalciuric patients with hypertension, especially when dietary control measures alone fail to adequately normalize urinary calcium excretion.
Other thiazide effects
Thiazides have many other effects on the body. These drugs increase serum calcium and uric acid levels while decreasing urinary citrate levels. Hyperuricemia or acute gout rarely develops in individuals receiving thiazides. A risk of dehydration, hypokalemia, and hyponatremia exists. They can cause magnesium loss and increase cholesterol. Adverse effects occur in about one third of patients but are usually mild. The most bothersome clinical adverse effect is lethargy, but muscle aches, depression, decreased libido, generalized weakness, and malaise also can occur. About 20% of patients stop thiazide therapy because of these adverse effects.
Thiazides tend to increase urinary volume because of their diuretic effect (which is a useful feature in kidney stone formers), but this can easily lead to dehydration if oral fluid intake is not maintained. Chemically, thiazides are sulfonamides and should not be generally used or should be used cautiously in patients with a history of sulfa allergy. Drug interactions have been reported when thiazides are used together with alcohol, barbiturates, narcotics, antidiabetic drugs, steroids, pressor amines, muscle relaxants, lithium, and nonsteroidal anti-inflammatory agents.
Thiazides 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.
Thiazide dosing
The dosage depends on the specific medication used. Once-a-day drug preparations are usually preferred because of better patient compliance and tolerability. Trichlormethiazide (Naqua) is administered as a 2- or 4-mg daily tablet. Indapamide (Lozol) can be administered in either 1.25 or 2.5 mg doses once a day. If a potassium-sparing combination is desired, those that contain triamterene, such as Dyazide, should be avoided, because triamterene can form its own stones. Moduretic, which uses amiloride as a potassium-sparing diuretic, would be recommended. Amiloride does not form stones and has a mild hypocalciuric effect of its own.
Most patients do not need any potassium supplementation, but potassium and electrolyte levels need to be checked periodically. Because of the risk of both hypokalemia and hypocitraturia, potassium citrate supplements are often prescribed along with thiazides in calcium stone formers.
Orthophosphates
In 1962, Howard et al first suggested the use of orthophosphate therapy (K-Phos Neutral, Neutra-Phos K, Uro-KP-Neutral) as a preventive treatment for kidney stones. The investigators noted that oral orthophosphates would turn the "evil" urine of a stone former into the "good" urine of a non–stone former.[22] Stone cessation rates of more than 90% have been reported with this agent.
Orthophosphate therapy has been shown to decrease urinary calcium excretion by lowering serum vitamin D-3 levels (which reduces intestinal calcium absorption) and by increasing renal tubular calcium reabsorption. Orthophosphates may also have some intestinal calcium-binding capability, but the limited studies conducted on this issue have not confirmed this effect.
Overall, orthophosphates lower 24-hour urinary calcium excretion by about 50% in patents with absorptive hypercalciuria and by about 25% in patients with other hypercalciuric states. No apparent effect on PTH levels exists in healthy individuals. Uncontrolled studies have shown kidney stone remission rates of 75-91% in recurrent stone formers on long-term orthophosphate therapy.
Orthophosphates also increase urinary stone inhibitors such as citrate and, particularly, pyrophosphate. Many patients (40% in one series) have even noted a loss of stone mass while on orthophosphate therapy. Orthophosphates are particularly useful in cases of absorptive hypercalciuria type III (renal phosphate leak) and when thiazides cannot be used or are ineffective. The use of orthophosphates together with thiazides is extremely effective in controlling urinary calcium excretion and reducing new kidney stone formation rates, particularly in hypercalciuric calcium oxalate stone formers.
About 60% of all dietary phosphate is absorbed in the duodenum and jejunum; 65% percent of the absorbed phosphate is excreted by the kidneys, and the rest is eliminated through the intestinal tract by secretion in the ileum and colon.
Adverse effects of orthophosphates
Adverse effects of orthophosphate therapy include diarrhea, bloating, and gastrointestinal upset. These adverse effects usually are worst during the first 2 weeks of therapy, after which they tend to diminish. The medication must be taken 3-4 times per day, which reduces patient compliance.
Do not administer to patients with struvite (magnesium ammonium phosphate) stones or to patients with renal failure, because they can develop soft-tissue calcifications. Use cautiously in patients with a history of predominantly calcium phosphate stones or in whom the urinary pH is consistently alkaline (which promotes calcium phosphate precipitation and stone formation). Patients with a previous history of gastrointestinal problems generally do not tolerate orthophosphate therapy well.
Currently available orthophosphate preparations tend to be rapidly dissolving, which increases the gastrointestinal upset and diarrhea. A slow-release form of potassium phosphate (UroPhos-K) is currently awaiting United States Food and Drug Administration (FDA) approval. This new preparation uses a wax matrix to slow the release of phosphate, reducing its adverse effects. It contains no sodium and is designed to modify urinary pH to 7.0, which discourages the formation of calcium phosphate crystals and calculi.
In a randomized, double-blind study, patients with absorptive hypercalciuria type I who were administered the new slow-release phosphate preparation had an average daily urinary calcium level of only 171 mg; controls averaged 288 mg/d.[23] Urinary inhibitor levels of citrate and pyrophosphate were increased in the group treated with orthophosphate, and no gastrointestinal adverse effects were reported.[23]
Orthophosphate dosing
To be effective, orthophosphates must be taken at regular intervals and in sufficient amounts. The neutral salt tends to have fewer adverse effects and is more effective than other preparations. Optimal levels of neutral orthophosphate are 1-2.5 g/d. Orthophosphate preparations for calcium stone formers should also be sodium free.
Bisphosphonates
Bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva) have become useful in the treatment of hypercalciuria and hypercalcemia. These agents are particularly helpful in cases of hyperparathyroidism in which parathyroid surgery cannot be performed or medical therapy is desired.
Bisphosphonates are analogues of pyrophosphate with a high affinity for the hydroxyapatite of bone, especially in areas of rapid turnover and bone resorption. These drugs inhibit osteoclast activity, which causes a net increase in bone density, calcium deposition, and mineralization. Preferential binding to osteoclasts is roughly 10 times greater than osteoblastic binding.
Although bisphosphonates are clearly helpful in cases of overt hypercalcemia and hyperparathyroidism, their usefulness in the long-term treatment of hypercalciuria in recurrent stone formers is unproved. These agents may be most useful in hypercalciuric stone formers in whom a history of decreased bone density or other evidence of osteoporosis, such as elevated osteocalcin levels, is present. Combination therapy with thiazides would be expected to be particularly beneficial. Bisphosphonates can also be helpful in difficult cases of hypercalciuria when other measures are unsuccessful or poorly tolerated.
Sodium cellulose phosphate
Sodium cellulose phosphate (Calcibind) is an extremely effective intestinal calcium-binding agent. This agent removes about 85% of the available intestinal calcium from the digestive tract and prevents its absorption. Sodium cellulose phosphate is about 11% sodium and has a calcium-binding capacity of 1.8 mmol of calcium per gram of cellulose phosphate. In the digestive tract, the sodium ion is exchanged for calcium, which is then excreted bound to the cellulose in the stool.
When sodium cellulose phosphate is used as a therapy, supplemental magnesium and a dietary oxalate restriction are recommended, because the cellulose phosphate binds magnesium as well as calcium and results in a magnesium deficiency if supplemental magnesium is not supplied. The need for the dietary oxalate restriction (primarily of tea, colas, coffee, green leafy vegetables, chocolate, and nuts) is due to the lack of available intestinal calcium that the cellulose therapy creates. With so much intestinal calcium bound to the cellulose, intestinal oxalate-binding sites are severely lacking. This leaves an excess of free, unbound intestinal oxalate available for absorption, which then increases oxaluria. To avoid this reactive enteric hyperoxaluria, a reasonable reduction in dietary oxalate is needed whenever sodium cellulose phosphate is used.
Unfortunately, sodium cellulose phosphate causes a reduction in absorbed calcium, which helps the hypercalciuria but may cause a negative calcium balance and subsequent reduction in bone density. It may still have a role in the diagnosis of hypercalciuria as a brief, therapeutic trial and in selected cases of absorptive hypercalciuria type I when other therapies are ineffective. The benefits of its use must be judged sufficient to justify the risks. Appropriate other treatments, such as thiazides and bisphosphonates, can be used to prevent unnecessary bone demineralization and limit the dosage of cellulose required so adverse effects and complications of its use are minimized.
Dipyridamole
Dipyridamole (Persantine) is a platelet adhesion inhibitor and vasodilator. It is usually used to lengthen platelet survival time and reduce the incidence of thromboembolic phenomenon after heart valve replacement surgery. Researchers have found that dipyridamole reduces renal phosphate excretion, which increases the serum phosphate level, resulting in decreased activation of vitamin D-3, then reduced hypercalciuria. This is useful in patients with vitamin D–dependent hypercalciuria, such as renal phosphate leak (absorptive hypercalciuria type III), especially when orthophosphates are not tolerated or cannot be used.
No direct effect on urinary calcium excretion is present. Adverse effects are minimal, but the medication must be taken frequently. Dipyridamole has been shown to reduce urinary calcium excretion in patients with vitamin D–dependent renal phosphate leak on a long-term basis.[24, 25]
Consultations
The treatment of hypercalciuria is important not only in the reduction of future kidney stone formation and the diagnosis of possible underlying metabolic disease but also in the prevention of bone demineralization and osteoporosis. Every physician who treats hypercalciuric patients may not be able to become an expert on this condition or its therapy. Physicians who are uncomfortable treating hypercalciuric patients should not hesitate to refer them, especially if the patients are highly motivated and interested in treating their calcium problem. A difficult or high-risk case that is resistant to dietary and standard medical therapy in a motivated patient would be a good case to refer to a physician expert or tertiary care center with expertise in this area.
Hyperparathyroidism cases should be referred to a physician skilled in dealing with this problem. Patients with overt renal failure need the assistance of a nephrologist.
With the general availability of kidney stone prevention testing protocols from most major reference laboratories, obtaining the necessary chemical studies is not problematic in the United States. (See Nephrolithiasis: Laboratory Evaluation of Stone Formers for a detailed discussion and evaluation of the various laboratories and their protocols.)
Absorptive hypercalciuria type I is a relatively rare condition, generally characterized by elevated urinary calcium and calcium/creatinine levels except while fasting. A variant of absorptive hypercalciuria type I exists in which fasting hypercalciuria can occur due to excess serum vitamin D-3. This vitamin D–dependent variant can be diagnosed with the finding of increased serum vitamin D levels and with correction of the fasting hypercalciuria with a trial of ketoconazole therapy. (Ketoconazole is a potent P450 3A4 cytochrome inhibitor that reduces circulating vitamin D-3 levels by 30-40%.) As many as 50% of all patients with absorptive hypercalciuria type I may have increased levels of vitamin D-3. Other causes of fasting hypercalciuria can be identified by elevated parathyroid (PTH) levels (renal calcium leak and hyperparathyroidism) or by increased urinary phosphate levels with hypophosphaturia (renal phosphate leak or absorptive hypercalciuria type III).
Absorptive hypercalciuria type I represents an extremely efficient intestinal calcium absorption mechanism. Bone density is usually normal, because abundant calcium is available for bone deposition, and PTH levels are normal or low. However, in some cases, the urinary calcium excretion is even greater than the amount absorbed, resulting in a net negative calcium balance and possible decrease in bone density, which is the opposite of what would be expected. Researchers think that this could be due to elevated serum vitamin D levels or just an increased sensitivity to vitamin D and its metabolites.
The diagnosis is usually clear in the traditional form of absorptive type I hypercalciuria, because normocalciuria is restored only during fasting and not on the 400-mg calcium 100-mEq sodium diet. The vitamin D–dependent variant can cause fasting hypercalciuria, something generally associated only with renal leak hypercalciuria and hyperparathyroidism. Serum PTH levels are elevated in both renal leak hypercalciuria and hyperparathyroidism but normal or low in absorptive hypercalciuria type I. Serum and urinary phosphate levels are normal, as well as vitamin D-3, which differentiates it from renal phosphate leak hypercalciuria.
Management
Treatment of absorptive hypercalciuria type I can be very difficult due to the severity of the intestinal calcium hyperabsorption. Therapy primarily consists of moderate dietary calcium restriction, thiazides, and orthophosphates.
Thiazides, such as trichlormethiazide (Naqua) or indapamide (Lozol), substantially reduce urinary calcium excretion, but they do not correct the primary defect, which is uncontrolled increased intestinal calcium absorption. Thiazides may lose their hypocalciuric effect over time and create hypokalemia, hypocitraturia, and increased uric acid levels.
Orthophosphates, such as K-Phos Neutral, Neutra-Phos K, and Uro-KP-Neutral, lower serum vitamin D-3 levels and reduce urinary calcium excretion. These agents are roughly equal to thiazides in their ability to reduce urinary calcium and prevent recurrent calcium stone formation. Because of the need for frequent dosing and various gastrointestinal adverse effects, orthophosphates are not the preferred agents when thiazides alone are sufficient and well tolerated. The combination of thiazides and orthophosphates used together may be necessary in difficult or resistant cases of absorptive hypercalciuria type I.
Sodium cellulose phosphate is an extremely potent intestinal calcium-binding agent that was previously recommended as a primary therapy for absorptive hypercalciuria type I, but concerns about creating a negative calcium balance, bone demineralization, and other adverse effects currently limit its usefulness. These risks have shifted therapy away from this agent in favor of thiazides and orthophosphates.
When sodium cellulose phosphate is used as a therapy, supplemental magnesium and a dietary oxalate restriction are recommended. This is because the cellulose phosphate binds intestinal magnesium as well as calcium. Supplemental magnesium therefore must be administered to patients on cellulose phosphate therapy to avoid magnesium depletion. The dietary oxalate restriction is due to the lack of free intestinal calcium that is created with the cellulose phosphate therapy. This removes the primary intestinal oxalate-binding agent (calcium) from the digestive tract and leads directly to increased free intestinal oxalate absorption with subsequent hyperoxaluria.
Alternative therapies
Other therapies include the use of increased dietary fiber, such as rice, oat, and wheat bran supplements, as relatively mild intestinal calcium binders. Bisphosphonates, such as alendronate (Fosamax), increase bone deposition of calcium, thus removing it from the circulation before it can be excreted. This improves bone calcium density and helps reduce urinary calcium levels. The main benefit may be in protecting the bones from calcium depletion and demineralization in hypercalciuric patients.
Optimization of all other urinary stone risk factors is highly recommended, including an increase in urinary volume, reduced dietary oxalate, and potassium citrate supplements as needed. Purine intake should be restricted if uric acid levels are elevated.
Pentosan polysulphate (Elmiron) has been suggested to be of some potential use in difficult calcium oxalate stone cases. Although it has no effect specifically on calcium excretion, pentosan polysulphate appears to reduce calcium oxalate crystallization and crystal aggregation, which reduces new kidney stone formation rates.[26, 27, 28]
Absorptive hypercalciuria type II is a less severe form of absorptive hypercalciuria. By definition, the hypercalciuria is controlled by a restricted low-calcium (400 mg calcium and 100 mEq sodium) diet. Fasting hypercalciuria is not present in this disorder.
Treatment is generally with dietary modifications, whenever possible, including a diet of moderate calcium intake. Overly strict dietary calcium restrictions are discouraged because of the possibility of creating a negative calcium balance and osteoporosis. Reduced dietary calcium causes a lack of oxalate-binding sites in the intestinal tract, which increases urinary oxalate levels, negating the benefit of any reduced urinary calcium.
Patients may decide they cannot follow the recommended calcium diet, or it may prove to be ineffective. In these cases, orthophosphates and/or thiazide therapy is recommended. Some concern exists that when thiazides are used in these cases on a long-term basis, the hypocalciuric effect may become attenuated as the calcium stores in the bones become filled. If this occurs, it generally occurs at least 2 years from the time of treatment initiation. A period of alternate therapy, such as sodium cellulose phosphate or orthophosphates, can be used temporarily for approximately 6 months, and then the thiazides can be restarted. No such problem exists with orthophosphate therapy, but current formulations need to be taken frequently and often have gastrointestinal adverse effects such as diarrhea, bloating, and indigestion.
Absorptive hypercalciuria type III, or renal phosphate leak hypercalciuria, is a vitamin D–dependent variant of absorptive hypercalciuria. This condition should be suspected in any hypercalciuric patient with a low serum phosphate level. A serum phosphate level of less than 2.9 mg/dL has been suggested as sufficient to raise the suspicion of renal phosphate leak hypercalciuria.
The etiology is an obligatory and uncontrolled loss of phosphate in the urine due to a renal defect. This produces hypophosphatemia, which stimulates the renal conversion of 25-hydroxyvitamin D to the much more active 1,25-dihydroxyvitamin D-3 (calcitriol, vitamin D-3). Vitamin D-3 increases intestinal phosphate absorption to correct the low serum phosphate levels. However, it also simultaneously increases intestinal calcium absorption. This extra calcium eventually is excreted in the urine. The diagnosis is confirmed by the following findings: (1) low serum phosphate, (2) hypercalciuria, (3) high urinary phosphate, (4) high serum vitamin D-3, and (5) normocalcemia and normal parathyroid hormone (PTH) levels.
Because the specific renal defect cannot be corrected, the most effective treatment is oral orthophosphate therapy. This corrects the hypophosphatemia and limits the amount of vitamin D-3 activation that occurs. The optimal orthophosphate supplement may be a slow-release neutral potassium phosphate (UroPhos-K), which has not yet been approved by the Food and Drug Administration (FDA). Dipyridamole (Persantine) also has been shown to increase the renal phosphate excretion threshold, which raises serum phosphate, normalizes high vitamin D levels, and reduces hypercalciuria.[24]
Renal leak hypercalciuria occurs in about 5-10% of calcium stone formers and is characterized by fasting hypercalciuria with secondary hyperparathyroidism but without hypercalcemia. This condition is generally not amenable to therapy with dietary calcium restrictions because of the obligatory calcium loss, which can easily lead to bone demineralization, especially if oral calcium intake is restricted.
The etiology is a defect in calcium reabsorption from the renal tubule that causes an obligatory excessive urinary calcium loss. This results in hypocalcemia, which causes an elevation in the serum parathyroid hormone (PTH). This secondary hyperparathyroidism raises vitamin D levels and increases intestinal calcium absorption. Essentially, this means that, even in cases of undeniable renal leak hypercalciuria, an element of absorptive hypercalciuria can be present.
The diagnosis is relatively easy. Any patient who fails to control their excessive urinary calcium on dietary measures alone and demonstrates relatively high serum PTH levels without hypercalcemia or hypophosphatemia probably has renal leak hypercalciuria.
Fasting hypercalciuria typically is found in this condition, renal phosphate leak, and in hyperparathyroidism. These can be differentiated by the presence or absence of hypercalcemia and hypophosphatemia. The calcium/creatinine ratio tends to be high in renal leak hypercalciuria (>0.20), and medullary sponge kidney is more likely than in other types of hypercalciuria.
Management
Treatment of renal leak hypercalciuria is primarily with thiazides. These medications specifically return calcium from the renal tubule to the serum, generally reduce urinary calcium levels by 30-40%, and eliminate the secondary hyperparathyroidism. This hypocalciuric effect of thiazides is diminished or eliminated if dietary sodium is not restricted. Adverse effects of thiazides include an increase in uric acid and a decrease in urinary citrate, and they also can cause hypokalemia. To correct these potential problems, potassium citrate often is administered to patients on long-term thiazide therapy. When used appropriately in renal leak hypercalciuria, thiazides work extremely well and do not appear to attenuate their hypocalciuric effect over time. Chemically, thiazides are sulfonamides and should be used cautiously, if at all, in patients with a known sulfa allergy.
Preferred forms of thiazide therapy include trichlormethiazide (Naqua) 2-4 mg/d and indapamide (Lozol) 1.25-2.5 mg/d. These 2 medications can be administered just once a day and tend to carry fewer adverse effects than shorter-acting thiazides. Potassium citrate is often added to the thiazide therapy to prevent hypokalemia and to increase urinary citrate levels. The dosage of potassium citrate should be adjusted based on serum potassium and 24-hour urinary citrate levels.
Resorptive hypercalciuria is almost always due to hyperparathyroidism. This generally accounts for 3-5% of all cases of hypercalciuria, although some reports have indicated an incidence as high as 8%. Increased parathyroid hormone (PTH) levels cause a release of calcium from bone stores. It also increases calcium absorption from the digestive tract by raising vitamin D-3 levels and decreases renal excretion of calcium by stimulating calcium reabsorption in the distal renal tubule. Eventually, the hypercalcemia overcomes this renal calcium–conserving quality and results in an increased net loss of calcium through the urine (hypercalciuria).
Hyperparathyroidism does not always result in calcium stone disease. The reason for this is unclear but may reflect optimal levels of other urinary metabolites, such as oxalate, uric acid, sodium, phosphate, citrate, urinary volume, and serum vitamin D-3 levels, among others. In some cases, the vitamin D-3 level has been suggested to be responsible for determining which patients with hyperparathyroidism actually develop kidney stones. This apparently reasonable hypothesis remains unproved. The current evidence suggests that vitamin D levels cannot be the only reason some hyperparathyroid patients develop stones while others do not.
Hyperparathyroidism produces a lower urinary calcium excretion for its level of serum calcium than hypercalcemia from other causes. In other words, for any level of serum calcium, hyperparathyroid patients have a lower urinary calcium excretion than hypercalcemic patients with normal PTH levels. This is due to the calcium-conserving effect of PTH on the kidneys.
The most common cause of hypercalcemia other than hyperparathyroidism is malignancy. Other causes include milk-alkali syndrome, Paget disease, sarcoidosis, multiple myeloma, and granulomatous diseases.
Hyperparathyroid patients who have parathyroid surgery and subsequently demonstrate normal urinary calcium levels are still at risk for developing stones at about the same rate as other calcium stone formers. Therefore, retesting with 24-hour urine determinations is recommended for calcium stone formers even after successful parathyroid surgery has normalized their serum calcium levels. Urinary cyclic adenosine monophosphate (AMP) can be used as a substitute for serum PTH level determinations to monitor patients who have already been diagnosed.
Hyperparathyroidism should be suspected in calcium stone–forming patients with significant hypercalciuria, even in those with only mild hypercalcemia. Failure to identify a curable cause of osteoporosis and calcium nephrolithiasis can be easily avoided just by checking the parathyroid hormone level routinely in hypercalciuric patients with relatively high serum calcium levels.[29]
Management
The recommended treatment for patients who produce calcium stones with hyperparathyroidism is parathyroid surgery. For those who are unable or unwilling to undergo the surgery, medical treatment is available. Bisphosphonates are the medical agents of choice, because they correct the hypercalcemia, reduce bone resorption, and lower urinary calcium excretion. Orthophosphates and calcitonin can be used for these patients as well. Thiazides should not be used in hyperparathyroid patients even when hypercalciuria is present because of the risk of increasing the hypercalcemia. (The only exception would be a short course for testing purposes in carefully selected cases to induce a mild, controlled increase in serum calcium while monitoring the PTH level to see if it drops appropriately or is autonomous.)
Estrogens should be used in postmenopausal, hypercalciuric women whenever possible. Their action is similar to the bisphosphonates.
PTH actually stimulates both osteoblastic and osteoclastic cells. High sustained levels of PTH result in a net loss of calcium and bone mass, but intermittent injections of PTH in animals and in human studies have indicated a net increase in osteoblastic activity and bone mass. This intermittent therapy, which appears promising as a potential treatment for osteoporosis, does not appear to significantly affect hypercalciuria or serum calcium levels.
Calcimimetic agents, such as cinacalcet (Sensipar), are a new and exciting modality being studied for the medical treatment of hyperparathyroidism.[30, 31, 32, 33, 34] Activation of specific calcium receptors on parathyroid cells by these calcimimetic agents inhibits PTH secretion. Essentially, the drug increases the sensitivity of calcium-sensing receptors.
Therapy with calcimimetic agents has already been used successfully in hyperparathyroid patients, particularly in those with chronic renal failure on dialysis with secondary hyperparathyroidism. A 50-60% decrease in circulating PTH and a mild decrease in serum calcium levels have been reported, but the hypercalciuria is not significantly affected. The agents may be also useful in resistant hypercalcemias and parathyroid cancers, as well as in the medical treatment of hyperparathyroidism.
Paricalcitol is a vitamin D analogue that was developed to help prevent and treat secondary hyperparathyroidism in patients with chronic renal failure. Actual vitamin D also suppresses parathyroid hormone levels but tends to cause hypercalcemia and hyperphosphatemia. Vitamin D analogues such as paricalcitol are able to significantly reduce parathyroid hormone levels without significantly changing serum levels or urinary excretion of either calcium or phosphorus.
Interestingly, the first hyperparathyroid patient treated with surgical removal of the parathyroids died of complications from his renal calculi.
Hypercalciuric stone formers have been demonstrated to have a lower average bone mineral density than non–stone formers matched for age and sex. Compared with normocalciuric stone formers, hypercalciuric patients have an average bone density that is 5-15% lower. This holds true for pediatric and adult populations, and the decrease of bone density occurs in the femoral neck (cortical) and lumbar spine (trabecular) areas. 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. 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, 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 (hyperparathyroidism), 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.
Hypercalciuric patients with known osteopenia, osteoporosis, or bone demineralization and those with untreated or unresponsive hypercalciuria should have periodic bone density measurements, especially if they are 50 years or older.
Patients on prolonged bedrest will lose bone density and develop hypercalciuria. This also occurs in astronauts during space flights of long duration. Studies on astronauts have shown an increase in their risk of kidney stone formation during prolonged weightlessness. These changes included hypercalciuria as well as decreased fluid intake and reduced urinary volumes.
Thiazide therapy can resolve the hypercalciuria in many of these patients and can also increase their bone density at a rate of 8% (spine) and 3% (hip) per year. Bisphosphonates and estrogen supplements also can be used.
An intriguing suggestion has been the possible use of osteocalcin levels before and after dietary calcium restriction.[35] Osteocalcin is released during periods of bone resorption, which would be expected with renal leak hypercalciuria, hyperparathyroidism, or any dietary calcium resistant hypercalciuria. Patients with elevated osteocalcin levels theoretically would benefit from thiazide and/or bisphosphonate therapy to prevent bone demineralization over time even if their hypercalciuria is well controlled with dietary therapy alone. Estrogen can be added in women. In other words, a high osteocalcin level could be a useful indicator of increased bone resorption, identifying those at the greatest risk of bone calcium loss. Appropriate therapy then could be used to prevent further bone demineralization and osteoporosis.
Management of hypercalciuria in osteoporosis
The issue of management of hypercalciuria can be complicated by the presence of osteoporosis or osteopenia. A serum calcium determination is the first step to identify patients with possible hyperparathyroidism. Elevated serum calcium levels should be followed up with a simultaneous parathyroid hormone (PTH) level to diagnose hyperparathyroidism.
Even without a history of calcium kidney stones, a 24-hour urine test to check urinary calcium excretion can be useful in the management of osteoporosis. If the patient has hypercalciuria (and hyperparathyroidism has been eliminated by serum testing), the patient will benefit from thiazide therapy, which increases serum calcium and reduces excessive urinary calcium excretion. As mentioned earlier, thiazides increase bone density in these patients.
Estrogen should be used, if appropriate, in postmenopausal women. Bisphosphonates, such as alendronate (Fosamax), risedronate (Actonel), or ibandronate (Boniva), should be used in men and in women when estrogen cannot be used.
Calcium supplementation can be helpful in osteoporosis, but urinary calcium levels need to be monitored carefully in calcium stone–forming patients, especially if they demonstrate overt hypercalciuria.
Studies have shown that, for most postmenopausal women with osteoporosis but with no previous history of calcium kidney stone disease, the overall risk of calcium nephrolithiasis does not increase significantly after supplemental calcium or combined calcium with calcitriol despite an increase in urinary calcium excretion.[9]
Calcium citrate is recommended for calcium stone formers in this situation, because its citrate component limits any increase in stone formation rate. Medical therapy, including thiazides, should be started first. Then calcium citrate can be added until the urinary calcium level reaches the normal upper limit (250 mg of calcium per 24 hours or 4 mg of calcium per kilogram of body weight).
Other treatment for possible urinary stone risk factors, such as uric acid, citrate, volume, phosphate, sodium, magnesium, and oxalate, should be optimized.
Repeat 24-hour urine testing and appropriate blood determinations are needed until the patient’s hypercalciuria is controlled and stable. Once this occurs, repeat testing can be performed less often. Testing once per year is considered reasonable for patients whose stone production and level of hypercalciuria are controlled. If hypercalciuria is not well controlled, appropriate adjustments can be suggested and testing should be repeated more frequently.
As patients modify their diets, they may substitute new foods and beverages for the ones previously restricted. These new dietary items have an unpredictable effect on the various stone risk factors. Therefore, follow-up 24-hour urine tests should include all of the major stone risk factors and not just calcium.
Routine radiographs, such as an abdominal flat plate (also called KUB for kidneys, ureters, and bladder) or plain renal tomograms, are useful to find any newly formed stones. This is particularly important and helpful in patients whose hypercalciuria is poorly controlled.
Some patients pass additional stones and assume their treatment plan is not working when, actually, these stones had already formed before testing or treatment began. Establishing the number, size, and location of any existing calculi before testing or treatment begins is important. In this way, patients can be reassured that their treatment plan is successful in controlling their hypercalciuria and they are only passing old, previously formed stones.
Patient education is extremely important in the treatment of hypercalciuria. Only a very motivated patient with an understanding of the need for continuing treatment can be expected to maintain any long-term preventive program, which typically lasts years. Additionally, no immediate penalty exists for cheating, such as occurs in a patient with diabetes who forgets to take his morning insulin. In a hypercalciuric patient who fails to follow the treatment regimen, the penalty (the next kidney stone) may not become apparent for many months or even years. This means that only a truly motivated and informed patient can be expected to follow any therapeutic program for hypercalciuria on a truly long-term basis.
Two excellent sources of general patient information on kidney stones and hypercalciuria include PK Pietrow and ME Karellas’s " Medical Management of Kidney Stones," available free online from American Family Physician, and the Institute of Diabetes and Digestive and Kidney Diseases.
For patients who desire more complete information, the National Institutes of Health (NIH) recommends The Kidney Stones Handbook by GR Savtiz and SW Leslie published by Four Geez Press.[36] This book includes a clearly written chapter on hypercalciuria as well as many other aspects of kidney stone disease that would be of great interest to patients with nephrolithiasis and their families. It can be ordered by phone (1-800-2-KIDNEYS [1-800-543-6397]), online (http://www.kidneystonesbook.net/), or by writing directly to the publisher at the following address:
Every patient with at least one kidney stone should be offered the opportunity for stone prevention testing and prophylactic therapy. This is most critical in children and in patients with renal failure or a single functioning kidney. For most adult patients, this is optional, but testing and preventive treatment needs to be offered and the consequences of additional preventable stones reviewed.
An excellent patient education book on nephrolithiasis is now available. Written by a urologist, the book is entitled The Kidney Stones Handbook and is recommended by the National Institutes of Health.[36] There are separate chapters on hypercalciuria and kidney stone preventive testing and treatment. For more information on this book, contact the publisher Four Geez Press at 1-800-2-KIDNEYS (1-800-543-6397), or send an email to gsavitz@earthlink.net.
Even if patients refuse preventive testing and prophylactic therapy, they should be advised of the potential risks of recurrent stones and be provided general dietary advice regarding moderation of calcium, animal protein, sodium, purines, and oxalate ingestion. All patients with history of kidney stones need to increase their fluid intake. Hypercalciuric patients must be cautioned about the risks of an overly severe reduction in oral calcium intake, which actually can increase their risk of new stone formation.
Do not fail to offer preventive testing and therapy to patients. Virtually all hypercalciuria patients can be helped if they are willing and able to follow a long term treatment program.
As noted earlier (see Overview of Hypercalciuria), a distinct possibility exists that something as basic as the definition of hypercalciuria may be flawed due to improper control groups used in establishing the original reference range for 24-hour urinary calcium excretion. If this proves to be correct, these values will need to be revised and their validity established. The addition of calcium/creatinine ratio and urinary calcium concentration to the standard 24-hour total urinary calcium excretion should be helpful in identifying hypercalciuric patients.
Molecular genetics and other research have indicated potential lines of future investigation into the nature of hypercalciuria. Avenues, such as mutations in the CLCN5 chloride channel gene or in the calcium-sensing receptor, appear promising. Other promising lines of research involve overexpression of vitamin D receptors and deficiencies in various renal tubular enzymes.
Parathyroid hormone (PTH) or its amino-terminal fragment has been shown to increase bone formation without causing hypercalcemia. PTH stimulates both bone formation and resorption. Once-daily injections of PTH tend to maximize the osteoblastic activity while minimizing bone resorption for a net gain in bone mass; this treatment was tested in a large, multicenter trial of 9347 postmenopausal women with osteoporosis. All of the patients received vitamin D and calcium supplementation.[37]
The group that received the PTH injections had reductions in fracture rates of 65-86%.[37] Urinary calcium excretion was increased only slightly (roughly by 30 mg of calcium per day in the treated group), but the overall incidence of hypercalciuria was no different between the PTH-treated group and placebo. This most likely was due to the single daily dosing of the PTH, which minimized the hypercalcemic and hypercalciuric responses.[37]
In short, this is a promising avenue of research for osteoporosis and osteopenia that appears to have no significant effect on hypercalciuria or calcium stone formation. Further research on this and other osteoblast-enhancing therapies hold promise in treating both osteoporosis and, possibly, select cases of hypercalciuria.
The ultimate goal is to develop therapies that eliminate the risk of calcium stone disease and osteoporosis from hypercalciuric individuals.
Stephen W Leslie, MD, FACS, Founder and Medical Director, Lorain Kidney Stone Research Center; Associate Professor of Surgery at Creighton University School of Medicine, Chief of Urology at Creighton University Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Martha K Terris, MD, FACS, Professor, Department of Surgery, Section of Urology, Director, Urology Residency Training Program, Medical College of Georgia; Professor, Department of Physician Assistants, Medical College of Georgia School of Allied Health; Chief, Section of Urology, Augusta Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Chief Editor
Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
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Bushinsky DA, Laplante K, Asplin JR. Effect of cinacalcet on urine calcium excretion and supersaturation in genetic hypercalciuric stone-forming rats. Kidney Int. May 2006;69(9):1586-92.
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No authors listed. Cinacalcet: new drug. Secondary hyperparathyroidism: where are the clinical data?. Prescrire Int. Jun 2006;15(83):90-3.
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