9730122, 254 PM hips femedicine medscape.comlaricle!2182757-print ‘medicine medscape.com Medscape Hypercalciuria Updated: Jun 02, 2021 ‘Author: Stephen W Leslie, MD, FACS; Chief Editor: Vecihi Batuman, MD, FASN Overview Practice Essentials Hypercalciuria, or excessive urinary calcium excretion, is the most common identifiable cause of calcium kidney stone disease. Idiopathic hypercalciuria is diagnosed when clinical, laboratory, and radiographic investigations fal to delineate an Underlying cause of the condition. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium, ‘The following are the most common types of clinically significant hypercalciuria: + Absorptive hypercalciuria + Renal phosphate leak hypercalciuia (also known as absorptive hypercalciuria type Il) + Renal leak hypercalciuria + Resorptive hypercalciuria - This is almost always caused by hyperparathyroidism Signs and symptoms ‘The morbidity of hypercalciuria is related to 2 separate factors; ie, kidney stone disease and bone demineralization leading to osteopenia and osteoporosis. Kidney stones are extremely painful because of the stretching, dilating, and spasm of the ureter and kidney caused by the acute obstruction, Hypercalciuric stone formers have been demonstrated to have a lower average bone mineral density than non-stone formers matched for age and sex. Moreover, compared with normocalciuric stone formers, hypercalciuric patients have an average bone density that is 5-15% lower [1] Pediatric patients In children, hypercalciuria is often associated with some degree of hematuria and back or abdominal pain and is also sometimes associated with voiding symptoms, Microcrystallization of calcium with urinary anions has been suggested to lead to injury of the uroepithelium in children with hypercalciuria. Consequently, when taking the history of the illness, attempt to identify symptoms relating to the urinary tract, paying special attention to the following signs and symptoms: Dysuria ‘Abdominal pain Irritability (infants) Urinary frequency Urinary urgency Change of urinary appearance Colic Daytime incontinence ‘+ Isolated or recurrent urinary tract infections + Vesicourethral reflux [51 al See Presentation for more detail Diagnosis Initial blood tests, such as serum calcium, creatinine, and phosphate studies, should be performed to identify patients at risk for hyperparathyroidism, renal failure, and renal phosphate leak. Once hyperparathyroidism has been excluded, diagnosis can be made using either a traditional or simplified workup. [4] hitpssfemeckcine.medscape.comiatiler2182757-print a2‘rg0122, 2:54 PM hips:femedicine medscape.comlaricle/21827S7-print In addition, imaging studies may be helpful in identifying underlying renal abnormalities or nephrolithiasis. Traditional workup Inthe traditional workup, an effort is made to formally study the exact cause of the hypercalciuria. Using this approach, a calcium-loading test is performed; results include the following: ‘+ Absorptive hypercalciuria - After calcium loading, periodically obtained urine samples tend to show a great increase in the patient's urinary calcium excretion + Renal leak hypercalciuria - After calcium loading, patients do not demonstrate as large an increase in urinary calcium as do those with absorptive hypercalciuria ified workup + Complete a medical history + Carryout inital blood and 24-hour urine testing + Identity hypercalciurie patients + Check hypercalcemic patients for hyperparathyroidism with parathyroid hormone (PTH) levels; consider a thiazide challenge test if the PTH level alone is inconclusive + Check hypophosphatemic patients for hyperphosphaturia and possible renal phosphate leak hypercalciuria; verify the diagnosis by determining of the vitamin D3 level or with a clinical trial of orthophosphate therapy + Start a therapeutic trial of dietary modification treatment ‘+ Repeat the blood and 24-hour urine tests See Workup for more detail Management Dietary therapy ‘The following are recommendations in the dietary treatment of hypercalcuria: ‘+ Limit daily calcium intake to 600-800 mg/day unless otherwise instructed (see the image below for alist of foods that are rich in calcium) Calcium-rich foods, hitpssfemeckcine.medscape.comiatiler2182757-print 21429730122, 254 PM hips femedicine medscape.comlaricle!2182757-print + 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/day) + Limit alcohol and caffeine intake ‘+ Increase fluid intake, especially water (sufficient to produce at least 2 L of urine per day) Pharmacologic treatment Medical therapy is used to treat hypercalciuria whenever dietary treatment alone is inadequate, ineffective, unsustainable, or intolerable for the patient. [5] Medications used in the treatment of hypercalciuria include the following + Diuretics - Thiazides, indapamide, and amiloride + Orthophosphates - Neutral phosphate + Bisphosphonates - Alendronate + Calcium-binding agents - Sodium cellulose phosphate; rarely used ‘See Treatment and Medication for more detail medicine Background Hypercalciuria, or excessive urinary calcium excretion, occurs in about 5-10% of the population{6] and is the most common identifiable cause of calcium kidney stone disease. Indeed, 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 also contributes to ‘osteoporosis, (Other significant causes of kidney stones include hyperoxaluria, hyperuricosuria, low urinary volume, and hypocttraturia,) Hypercalciuria can be classified as idiopathic or secondary. idiopathic hypercalciuria can be diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium, (See Pathophysiology, Etiology, and Workup.) Elevated urinary calcium occurs by 1 of 3 primary mechanisms, as follows: ‘+The filtered load of calcium is abnormally increased without an adequate compensatory increase in tubular calcium reabsorption + The filtered calcium load is normal but tubular calcium reabsorption is reduced ‘+ The filtered load is increased and the reabsorbed load is reduced ‘A good screening test for hypercalciuria compares the ratio of urinary calcium to creatinine. To validate the screening test, an accurately timed urinalysis should be used to confirm any positive screens, (See Workup.) 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 excass 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 diet (400 mg calcium and 100 milliequivalent [mEq] sodium). Table 1, below, oullines the various definitions of hypercalciuria based on a regular of restricted diet, Table 1. Definitions of Hypercalciuria (Open Table in a new window) Diet Definition Regular diet (unrestricted) Women: Urinary excretion >250 mg calcium (6.2 mmolV24 h) hitpssfemedkcine.medscape.comiatiler2182757-print 3142730122, 254 PM hips femedicine medscape.comlaricle!2182757-print Men: Urinary excretion >275-300 mg calcium (7.5 mmol/24 h) Urinary excretion >4 mg calcium (0.1 mmol) per kilogram of body weight per day Urinary concentration >200 mg calcium per liter Urinary excretion >200 mg calcium per day Restricted diet (400 mg calcium, 100 mEq sodium) Urinary excretion >3 mg calcium per kilogram of body weight per day Limitations of hypercalciuria definitions Optimal levels of urinary calcium have not been determined. 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 in research investigations of recurrent stone formers in the healthy group of study subjects and by poorly defined controls.(7] 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. ‘Therefore, 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.(7] Further study is needed to confirm these conclusions and to possibly establish better 24-hour urine reference ranges for calcium and other metabolic stone-risk chemistries. (See Workup.) Clinically significant hypercalciuria The following are the most common types of clinically significant hypercalciuria, although evidence suggests that this classic differentiation is insufficient to explain all of the cellular and genetic variations that have been noted in the condition(6] + Absorptve hyporcaleiuria + Renal phosphate leak hypercalciuria (also known as absorptive hypercalciuria type Il) + Renal leak hypercalciuria + Resorptive hypercaleiuria Itis uncertain whether these different types of hypercalciuria are truly separate and distinct entities or are instead 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 litle impact, clinically, because ultimately whatever therapy works is required, Table 2, below, provides simple test guidelines for specific diagnoses of hypercalciuria, (See Treatment and Medication.) Table 2. Hypercalciuria Simplified Test Guideline (Open Table in a new window) Urinary Calcium on 400- Fasting Post-Calchum Load mg Caleium Diet Calcium/Creatinine Hypercalciuria Diagnosis (mg/dL) Ratio CalciumiCreatinine Ratio (Normal = < 200 mg/24 -< h) (Normal =< 0.11) (Normal = < 0.20) Normal Normal Normal Normal hitpssfemedicine.medscape.comiatiler2182757-print aa730122, 254 PM hips Jemedicine medscape.comlaricle!2182757-print Absorptive type | High Normal High Absorptive type Il Normal Normal High Absorptive type Ill (renal 4, i i phosphate leak) High High High Renal leak High High High Resorptive i i : (hyperparathyroidism) High High High 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-atkali syndrome). Calcium absorption occurs mainly in the duodenum and normally represents only about 20% of the ingested dietary calcium load [8] 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 hypercaleiuria, 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. Type! Absorptive hypercalciuria type | is a relatively rare condition, generally characterized by elevated urinary calcium and calcium/creatinine levels except while fasting, Avvariant of absorptive hypercalciuria type | exists in which fasting hypercalciuria can occur due to excess serum vitamin D3, 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 D3 levels by 30-40%.) ‘As many as 50% of all patients with absorptive hypercalciuria type | may have increased levels of vitamin D3. Other causes of fasting hypercalciuria can be identified by elevated PTH levels (renal leak and resorptive hypercalciuria) or by increased urinary phosphate levels with hypophosphaturia (renal phosphate leak calciuria, also called absorptive hypercalciuria type up, Absorptive hypercalciuria type | 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. In some cases, however, 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 may be the result of an increased sensitivity to vitamin D and its metabolites. Type Il This is a less severe form, and most common variety, of absorptive hypercalciuria. It usually responds to moderate dietary calcium restriction. Fasting hypercalciuria is not present in this disorder. ‘Type Ill Absorptive hypercalciuria type Ill, also called renal phosphate leak hypercalciuria, is a vitamin D-dependent variant of absorptive hypercalciuria. This condition, a relatively uncommon cause of hypercalciuria, should be suspected in any patient hitpssfemeckcine.medscape.comiatiler2182757-print sia9730122, 254 PM hips femedicine medscape.comlaricle!2182757-print with hypercalciuria who has 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, with a low ratio of tubular maximum reabsorption of phosphate to glomerular fitration rate.[9] This produces hypophosphatemia, which stimulates the renal conversion of 25-hydroxyvitamin D to the much more active 1,25-dihydroxyvitamin D3 (calcitriol, vitamin D3), Vitamin 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. Low serum phosphate Hypercalciuria High urinary phosphate High serum vitamin D3 Normocalcomia and normal PTH levels, Renal leak hypercalciuria Renal leak hypercaleiuria occurs in about 5-10% of calcium-stone formers and is characterized by fasting hypercalciuria with secondary hyperparathyroidism but without hypercalcemia, ‘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 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 who demonstrates relatively high serum PTH levels without hypercalcemia or hypophosphatemia probably has renal leak hypercalciuria, ‘The ratio of calcium to creatinine (in mg/dL) tends to be high in renal leak hypercalciuria (> 0.20), and the occurrence of medullary sponge kidney is more likely than in other types of hypercalciuria, Renal leak hypercalciuria 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. Resorptive hypercalciuria 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 PTH levels cause a release of calcium from bone stores. In addition, resorptive hypercalciuria increases calcium absorption from the digestive tract by raising vitamin D3 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 urinary volume and optimal levels of other urinary metabolites, such as oxalate, uric acid, sodium, phosphate, citrate, urinary volume, and serum vitamin D3, In some cases, the vitamin D3 level has been suggested to be responsible for determining which patients with hyperparathyroidism actually develop kidney stones. This apparently reasonable hypothesis remains Unproved, however, and the current evidence suggests that vitamin-D levels cannot be the only reason that some patients with hyperparathyroidism do not develop stones. Hyperparathyroidism produces a lower urinary calcium excretion for the patient's serum calcium level than does hypercalcemia from other causes. In other words, for any level of serum calcium, patients with hyperparathyroidism have lower urinary calcium excretion than do patients with hypercalcemia who have normal PTH levels: This is due to the calcium-conserving effect of PTH on the kidneys. Diagnosis and treatment Hyperparathyroidism should be suspected in calcium stoneforming patients with significant hypercalciuria, even in those with only mild hypercalcemia, Failure to identify a curable cause of asteoporosis and calcium nephrolithiasis can be easily avoided just by checking the parathyroid hormone level routinely in hypercalciuric patients with relatively high serum calcium levels [10] Patients with hyperparathyroidism who have parathyroid surgery and subsequently demonstrate normal urinary calcium levels are stil 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 (cAMP) can be used as a substitute for serum PTH level determinations to monitor patients who have already been diagnosed. hitpssfemedicine.medscape.comiatiler2182757-print e1429730122, 254 PM hips femedicine medscape.comlaricle!2182757-print @medicine Pathophysi logy Urinary excretion of calcium is the result of the complex interplay of the gastrointestinal tract, the kidney, and bone and is regulated by multiple hormones. Hypercalciuria is believed to be a polygenic trait and is significantly influenced by diet. Idiopathic hypercalciuria is the most common metabolic abnormality in patients with calcium kidney stones. Subjects with idiopathic hypercalciuria have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, a negative calcium balance is commonly seen in balance studies, especially in patients on a low-calcium diet. ‘The mediator of decreased renal calcium reabsorption is unclear; itis not associated with either an increase in fitered renal calcium or altered parathyroid hormone (PTH) levels. ‘An increased incidence of hypercalciuria is observed in first-degree relatives of individuals with idiopathic hypercalciuria, but it appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion, Increased tissue vitamin D response may be responsible for manifestations of idiopathic hypercalciuria in at least some patienis.[11, 12] Moreover, deficiency in the enzyme that inactivates 1,25(OH)2D, 1,25(OH)2D-24 hydroxylase causes elevated vitamin D, hypercalciuria, nephrocalcinosis, and kidney stones.[13] Furthermore, dysregulation of the calcium- sensing receptor—Claudin-14 axis likely contributes to the development of hypercalciuria(14, 15, 16] Intestinal adaptation 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 dally dietary calcium ingestion increases urinary calcium levels by 8 mg/day in a healthy population but raises urinary calcium levels by 20 mg/day in hypercalciuric patients. medicine Etiology ‘When properly evaluated, 97% of hypercalciuric patients can be classified according to etiology. Causes of hypercalciuria that need to be considered include the following: 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 Milk-alkali syndrome ‘Wong and colleagues reported that hypercalciuria was present in 91.9% of subjects on deferasirox, an oral iran chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies but was not present ina control group taking an alternative iron chelator, deferoxamine.[17] Mabyar et al reported a significantly higher frequency of hypercalciuria and hyperuricosuria in children with vesicoureteral reflux (VUR) than in a control group. These authors also observed a positive correlation between hypercaleiuria and hyperuricosuria and severity of VUR (P <0.05).[18] ‘As the name implies, the cause of idiopathic hypercalciuria is not known, Several theories have been published, and some data supports certain aspects of these theories; however, these theories cannot yet be uniformly applied to a large patient hitpssfemedicine.medscape.comiatiler2182757-print a29730122, 254 PM hips femedicine medscape.comlaricle!2182757-print Population. Studies that examined metabolic balance have reported increased absorption of calcium from the intestine. In some instances, this process has been shown to be independent of vitamin D or a result of increased gut sensitivity to vitamin D. In other patients with hypercalciuria, the proportion of calcium excreted into the urine is higher than normal, regardless of dietary intake of calcium. In fact, some patients have been found to have higher than normal urinary calcium despite lower than normal dietary intake, suggesting decreased renal tubular reabsorption. This renal tubular leak is possibly a result of a mutational defect in 1 or more ion channels. Another proposed mechanism involves an imbalance of calcium deposition and reabsorption in bone that is independent of PTH or vitamin D. In addition, a combination of these factors may contribute to the high amounts of urinary calcium ‘observed in patients with idiopathic hypercalciuria Genetics Molecular genetics and other research have indicated potential lines of future investigation into the nature of hypercalciuria, For example, dysregulation of the calcium-sensing receptor—claudin-14 axis, as well as polymorphism in the regulatory region controlling expression of the calcium-sensing-receptor gene, may contribute to increased calcium excretion.[14, 15] More than 60 activating mutations in the calcium-sensing receptor have been identified to cause autosomal dominant hypocalcemic hypercalciuria.{19] Familial hypomagnesemia with hypercalciuria and nephrocaleinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in the tight junction proteins claudin-16 and claudin-19, which are encoded by the CLON16 and CLDN19 genes, respectively. Over 60 mutations in CLON16 have been described in FHHNC. The disorder is characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure [20] ‘An interesting study in specially prepared transgenic mice suggests the possible importance of the gene CLCNS, which encodes CICS (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 CICS so that these mice lacked CICS activity. [21] This mouse model is similar to Dent disease in humans, which is a rare, heritable X-linked disorder with reduced CICS activity that is characterized by absorptive 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.(21] Other promising lines of research involve overexpression of vitamin D receptors and deficiencies in various renal tubular enzymes, Obesity The association between obesity and kidney stones has been well documented inthe literature.{22, 23] Pregnancy 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 al 3 trimesters. In addition, urinary oxalate, magnesium, and citrate levels have been found to increase during pregnancy. This suggests that the overall risk of nephroihiasis during pregnancy may not be increased substantially, as levels of urinary stone promotors and inhibitors have both been found to rise. Calcium supplementation ‘A study suggests that calcium supplementation, with or without calcitriol, does not increase the risk of calcium urolithias significantly in healthy (non-stone-forming) postmenopausal women even if they have increased urinary calcium excretion. [24] The study, which involved healthy postmenopausal women (not calclum-stone formers), showed that those women who ‘were administered calcium supplements alone did not demonstrate any significant increase in their urinary calcium excretion, ‘Those who were administered calcium and calcitriol did have a significant increase in their urinary calcium levels. 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. Theoretically, a thiazide diuretic would reduce the urinary excretion of calcium and could be of some therapeutic beneft for this group at risk for osteoporosis. Vitamin D Many cases of absorptive hypercalciuria involve elevated vitamin-D levels.{8] Vitamin D increases small-bowel absorption of calcium and phosphate, enhances renal filtration, decreases PTH levels, and reduces renal tubular calcium absorption, which ultimately leads to hypercalciuria, An elevated vitamin-D level accounts for the finding of fasting hypercalciuria in some cases of absorptive hypercalciuria type |. About 30-40%, and possibly as many as 50%, of patients with absorptive hypercalciuria demonstrate abnormally elevated vitamin D3 levels. hitpssfemeckcine.medscape.comiatiler2182757-print ia9730122, 254 PM hips femedicine medscape.comlaricle!2182757-print Ithas been suggested that some patients have an exaggerated response to, affinity for, or sensitivity to normal levels of vitamin D and its metabolites. Activation of vitamin D3 takes place in the proximal renal convoluted tubule. This activation can be reduced by ketoconazole therapy. 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 chronie disease that causes granulomas in various parts of the body but most often 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 patients with sarcoidosis, 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 therapy usually controls the hypercalcemia and hypercalciuria. Primary hyperparathyroidism has been reported in some patients with sarcoidosis [25] @medicine Epidemiology 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 among 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. Its 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 among various 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. International occurrence Globally, the overall risk of forming stones differs in various regions. The probability is 1-6% 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 where diets are high in animal protein, whereas bladder stones are predominant in developing countries and are related to poor socioeconomic conditions. Race-related demographics White persons tend to have stones more often than do black individuals. Whether this is due to genetic differences or is ‘secondary to dietary and socioeconomic factors is unclear, although the latter explanation 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 [26] The investigators compared lithagenic risk factors in healthy black male volunteers, black males who were recurrent stone formers, and white male 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,[26] 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 {27} ‘Asstudy 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 [28] The results of a high-oxalate diet also differed between the black and white groups [28] Sex-related demographics ‘The reference range of urinary calcium excretion for men generally is 275 mg or less per day, whereas in women the usual dally imitis only 250 mg, These reference values were created using large numbers of people (not calcium kidney-stone hitpssfemeckcine.medscape.comiatiler2182757-print 91429730122, 254 PM hips femedicine medscape.comlaricle!2182757-print 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. Cleatly, stone development occurs when the chemical conditions are favorable, regardless of what any arbitrary reference range might be. For most practical purposes, the 250-mg/day limit for 24-hour urinary calcium excretion or a concentration ‘of no more than 200 mg of calciumllter 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). Postmenopausal women are more likely than men to demonstrate hypercalciuria. Hyperparathyroidism, which produces hypercalciuria, is more common in older women, and, because of concerns about their risk for osteoporosis, calcium supplementation is more popular with women. Ina study, women who developed calcium kidney stones had an average calcium intake that was 250 mgiday 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. When urinary chemistry and stone formation rate data were analyzed with the demographic information from a large national database of kidney stone formers, investigators 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 and 51,000 men in the Health Professionals Follow-up Study. Investigators at Harvard who conducted these 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.{7] 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 B6 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 B6 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 benef to dietary vitamin-C modifications in either men or women.) ‘As previously mentioned, 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. Age-related demographics ‘The peak age range for calcium kidney stone production is generally 35-45 years. Another peak incidence of hypercalciuria ‘occurs in postmenopausal women. In this older age group, many women are taking supplemental calcium for asteoporosis, prophylaxis or therapy. The excess absorbed calcium eventually is released into the urine. In addition, postmenopausal ‘women are al 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 types of risk factors, as well as the risk of recurrent stones, are similar to those for 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. Children Hypercalciuria can occur at any age, including in newboms. The peak incidence of idiopathic hypercalciuria in children ‘occurs at age 4-8 years. medicine Prognosis ‘The morbidity of hypercalciuria is related to 2 separate factors; le, 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, yonephrosis (infection proximal to the obstruction), and intractable pain not relieved by parenteral analgesics, Bone-density loss hitpssfemedicine.medscape.comiatiler2182757-print 101429730122, 254 PM hips femedicine medscape.comlaricle!2182757-print Hypercalciuric stone formers have been demonstrated to have a lower average bone mineral density than non-stone formers matched for age and sex. Moreover, compared with normocalciuric stone formers, hypercalciuric patients have an average bone density that is 5-15% lower 1] (In children with idiopathic hypercalciuria, bone mineral-density measurements. have consistently demonstrated Z-score reductions at the lumbar spine and, to a lesser extent, the femoral neck [29] ) Bone loss is worsened if patients are placed on a calcium-restricted diet, as 99% of the body's calcium is stored in the bones. Fortunately, significant clinical bone loss is relatively rare. However, female hypercalciuric stone formers who become menopausal are at significantly greater risk of osteoporosis than their healthy female counterparts. The higher the Urinary calcium excretion is, the greater the risk. Untreated patients with an obligatory urinary calcium loss relatively unaffected by diet, as in renal leak hypercalciuria, renal phosphate leak, and resorptive hypercalciuria, develop a negative calcium balance that can result in osteopenia or osteoporosis, ‘Some patients may have a primary altered bone metabolism, as occurs in postmenopausal women with an estrogen deficiency. Thirty percent of hypercaleiuric 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. medicine Patient Education 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/her ‘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 long-term basis. For patient education information, see Kidney Stones. Other excellent sources of general patient information on kidney ‘stones and hypercalciuria include PK Pietrow and ME Karellas’s " Medical Management of Common Urinary Calcul,” available free online from American Family Physician, and the National institute of Diabetes and Digestive and Kidney Diseases (NIDDK). @medicine Presentation History Note that hypercalciuria has no significant physical examination findings and is purely a laboratory diagnosis. Important aspects of the patient's history may include the following: + Skeletal diseases (eg, osteoporosis, Paget disease) may produce hypercalciuria ‘+ Immobilization for various reasons (eg, postoperative, orthopedic injury, burns, intensive care, spinal cord injury, bone marrow transplants) can cause rapid bone remodeling and, hence, elevated calcium excretion; fortunately, this has become less common owing to the use of early mobilization strategies and physical therapy + Nephrolithiasis is commonly associated with hypercalciuria ‘+ Malignancy is a common cause of hypercalcemia and hypercalciuria in hospitalized patients; it usually results from bone destruction, bone reabsorption, or humoral factors such as PTH-related protein. ‘+ Human immunodeficiency virus (HIV) infection or its treatment may be associated with a higher risk of hypercalciuria in children Me ations Certain medications, such as vitamin-D supplements and furosemide, may contribute to hypercalciuria, All loop diuretics decrease the tubular reabsorption of calcium [30] Dietary and fluid intake hitpssfemeckcine.medscape.comiatiler2182757-print weeargo, 2:84 Pm Npsilemedicine medscape conlartll2 82757 -print Many dietary factors can alter urinary calcium excretion, including the following: + Sodium chloride + Protein + Glucose + Sucrose + Magnesium + Phosphate ‘An inverse relalionship between phosphate intake and urinary calcium excretion is observed: thus, phosphate-restricted diets result in an increase in urinary calcium excretion. With all of the other dietary items mentioned above, a direct relationship between dietary intake and urinary calcium excretion is observed. Far history Idiopathic hypercalciuria can run in families, as can diseases that are associated with secondary hypercalciuria. Approximately 50% of persons with kidney stones and hypercalciuria have a first-degree relative who also has hypercalciuria, Signs and symptoms in children In children, hypercalciuria is often associated with some degree of hematuria and back or abdominal pain, and is also somelimes associated with voiding symptoms. The standard treatment for pediatric hypercalciuria is limited to dietary or short-term medical therapy, because the patients become asymptomatic when the hypercaleiuria is corrected and are often lost to follow-up, A study involving 124 children with idiopathic hypercalciuria found that 50% of these patients had a family history of kidney stone disease. Fifty-two children developed clinical symptoms of flank or abdominal pain during the study period, but only 6 of these children had actual renal calcull. Twenty-seven children had hematuria, and 10 had incontinence. The children were treated with increased fluid intake and a reduction in dietary oxalate and sodium. Some required treatment with thiazides. All but 5 of the patients responded to therapy. Resolution of the hypercalciuria eliminated the recurrent pain in this patient population, [31] Another study, looking at the long-term effects of hypercalciuria in children and several possible therapies over a 4- to 11- year period, concluded that, regardless of treatment, most children with hypercalciuria eventually become asymptomatic while remaining hypercalciuric [32] Because limiting calcium intake in children is unwise, the recommended dietary therapy for hypercalciuria is to use a low-sodiumv/high-potassium diet, which normalizes the hypercalciuria in most pediatric patients, In children with hypercalciuria, microcrystallization of calcium with urinary anions has been suggested to lead to injury of the Uuroepithelium. Consequently, when taking the history of the illness, attempt to identify symptoms relating to the urinary tract. Pay particular attention to the following signs and symptoms: + Dysuria ‘Abdominal pain ‘Irritability (infants) * Urinary frequency + Urinary urgency ‘+ Change of urinary appearance + Colic ‘+ Daytime incontinence + Isolated or recurrent urinary tract infections(2} + Vesicourethral reflux(3] ‘Some clinical manifestations are age dependent. For instance, irtability may be the only manifestation in infants, but a teenager may experience renal colic and hematuria. medicine hitpssfemeckcine.medscape.comiatiler2182757-print 12429730122, 254 PM DDx hips:femedicine medscape.comlaricle/21827S7-print Diagnostic Considerations ‘The following conditions are included in the differential diagnosis of hypercalciuria: + Dentgisease + Hypercalcemia + Hypercaleemic nephropathy + Hyperoxaluria + Hyperparathyroidism + Hypervtaminosis D + Hypophosphatemia + Nophrocaleinosis + Nephrolithiasis + Acute renal colic + Osteoporosis + Pyelonephriis + Rickets + Sarcoidosis + Uric acid stones + Urinary tract infection + Uroiithiasis + Wilms tumor + Xanthinuria Differential Diagnoses + Acute Poststreptococcal Glomerulonephritis + Bartter Syndrome * Disorders of Bone Mineralization + Enuresis| + Hematuria ‘+ Hypophosphatemic Rickets + IgA Nephropathy + Juvenile Idiopathic Arthritis + Medullary Sponge Kidney + Nephritis medicine Workup Workup hitpssfemedicine.medscape.comiatiler2182757-print 139429730122, 254 PM hips femedicine medscape.comlaricle!2182757-print Approach Considerations Many different processes and disease states can produce overlapping symptoms and similar findings on urinalysis. A directed, stepwise approach is important in the evaluation of a patient with symptoms or a history compatible with hypercalciuria to avold unnecessary expense, exposure to radiation, and patient discomfort. The first task is to document hypercalciuria. Looking for commonly associated urinary findings or problems that can produce similar symptoms is easy and inexpensive. ‘Two distinct approaches to the laboratory evaluation of hypercalciuric patients exist: the traditional approach and the simplified clinical approach, With both, initial blood tests, such as serum calcium, creatinine, and phosphate studies, should be performed to identify patients at risk for hyperparathyroidism, renal failure, and renal phosphate leak. Once hyperparathyroidism has been excluded, the 2 approaches differ [4] In the traditional approach, an effort is made to formally study the exact cause of the hypercalciuria, ultimately establishing a more precise diagnosis and leading directly to the most appropriate therapy based on etiology. ‘The simplified clinical approach uses a goal-oriented focus with therapeutic trials of therapy. A precise diagnosis may not be determined by this system. Pediatric patient approach A directed stepwise approach is important in the evaluation of a child with symptoms or a history compatible with hypercalciuria in order to avoid unnecessary expense, exposure to radiation, and patient discomfort. The first task is to document hypercalciuria, Looking for commonly associated urinary findings or problems that can produce similar symptoms is also easy and inexpensive. Consequently, the initial approach to any child with urgency, hematuria, or suspected hypercalciuria should include urinalysis, urinary calcium, creatinine, and uric acid Differentiation between absorptive hypercalciuria types | and II ‘The fasting and post-calcium-loading parameters are essentially the same in these 2 entities. The main difference is that patients with absorptive hypercalciuria type | still have hypercalciuria, defined as urinary excretion in excess of 200 mg of calcium per 24 hours, while on a 400-mg low-calcium diet. Patients with absorptive hypercalciuria type Il have a less severe form of calcium hyperabsorption and are able to achieve normal urinary calcium levels while on the low-calcium diet Essentially, ifthe patient demonstrates normocaleiuria on the restricted calcium diet, further testing is unnecessary because absorptive hypercalciuria type Il is the only disorder that normalizes urinary calcium excretion on a limited oral caicium diet Differentiation of absorptive from renal leak hypercalciuria without a calcium-loading test Patients with renal leak hypercalciuria tend to have relatively low serum calcium levels in relation to their serum parathyroid hormone (PTH) levels. Secondary hyperparathyroidism caused by an obligatory loss of serum calcium is a hallmark of renal leak hypercalciuria. The calcium/creatinine ratio tends to be high (> 0.20) in patients with renal calcium leak, and these individuals are more likely than other hypercalciuric patients to have medullary sponge kidney. Atrial of dietary therapy with a restricted calcium diet is relatively ineffective with renal leak hypercalciuria and is quite harmful in the tong term because of possible bone decalcification, negative calcium balance, and osteoporosis. Alkaline phosphatase and cyclic adenosine monophosphate (cAMP) levels are often elevated in this condition. Thiazide challenge ‘Thiazides, the mainstay of pharmacologic therapy for hypercalciuria, increase serum calcium levels. Therefore, they can be Used in a thiazide challenge for cases of borderline or subtle hyperparathyroidism to confirm the diagnosis. This involves the temporary use of thiazide therapy to create a controlled hypercalcemia. Ifthe PTH levels drop, the patient is responding property and hyperparathyroidism is unikely. I the PTH level does not diminish as the serum calcium level rises, hyperparathyroidism can be diagnosed. medicine Tradi jonal Workup Inthe traditional classification system, several distinct types of hypercalciuria exist, such as absorptive hypercalcluria types 1,1 and Ill; renal leak hypercalciuria; and resorptive hypercalciuria. This classification system assumes that these hypercalciurias are separate and distinct entities that can and should be differentiated. In clinical practice, these hypercalciuria types often overtap, 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, hitpssfemeckcine.medscape.comiatiler2182757-print aiaasys0tz2, 2:54 >M Hips femedine macscapa com/arle2182757-pxnt Calcium-loading test In the traditional diagnostic approach, a calcium-loading testis performed, with the type of hypercalciuria determined in the following ways: ‘+ Absorptive hypercalciuria - During a defined period of fasting, patients with absorptive hypercalciuria show a significant decrease in urinary calcium excretion; patients are then administered a large oral calcium meal, with urine samples obtained periodically afterwards tending to show a great increase in the patient's urinary calcium excretion, + Renal leak hypercalciuria ~ In this type, the kidney has an obligatory calcium-losing defect, so patients are expected to show relatively litle effect from dietary measures alone, including fasting; following a large oral calcium meal, patients with renal leak hypercalciuria do not demonstrate as large an increase in urinary calcium as do those with absorptive hypercalciuria In practice, however, performing the calcium-loading test is difficult, tedious, and usually reserved for selected cases in a tertiary care center or for research purposes, @medicine Simplified Workup An alternate approach to the diagnosis of hypercalciuria is based on patients’ clinical responses, This simplified clinical approach is much easier and more practical for the vast majority of physicians and patients. In this system, initial blood and 24-hour urine testing is performed, but the finding of hypercalciuria does not automatically require further testing, such as a calcium-loading test, to determine the exact etiology of the excess urinary calcium. Instead, a trial of therapy is instituted, usually based on dietary guidelines (after frst screening the patient with blood tests for kidney failure, hyperuricemia, hypophosphatemia, and hypercalcemia). ‘The clinical response is evaluated with repeat 24-hour urine testing. If the hypercalciuria has resolved after dietary changes alone, the treatment plan is judged adequate and can be continued. If the response to dietary measures is insufficient, additional medical treatment is necessary. Blood and 24-hour urine testing is repeated at periodic intervals of 30-90 days. Longer intervals emphasize patient compliance, while shorter periods stress efficacy. Appropriate treatment modifications are suggested until the results are stable, with acceptable urinary risk-factor levels. Not only is the simplified clinical method much easier to perform and follow than the traditional workup, it also corresponds to what many experts actually carry out in their own clinical practices. The precise diagnosis may not always be clear, but the patient receives essentially the same treatment without the need for an inconvenient expensive test that is hard to interpret. Advantages of the simplified approach With the simplified approach, only a short-term trial of dietary therapy is needed to determine whether dietary modification is potentially adequate as a treatment. Medical treatment, usually beginning with thiazides, is used if dietary therapy alone is Unsuccessful for any reason, Serum testing for PTH excess, hypercalcemia, and hypophosphatemia helps to identify those entities (hyperparathyroidism, renal leak hypercalciuria, renal phosphate leak) that should not be treated with dietary therapy alone. ‘The vast majority of hypercalciuric patients can be treated with this simplified plan. Ensuring that patients are retested while ‘on the modified diet is important; otherwise, judging the effectiveness of the therapy or patient compliance is impossible, Summary of the simpitied approach ‘The simplifed approach is carried out as follows + Complete a medical history + Carry out inital blood and 24-hour urine testing + Identity hypercaleiuric patients + Check hypercalcemic patients for hyperparathyroidism with PTH levels; consider a thiazide challenge test if the PTH level alone is inconclusive + Check hypophosphatemic patients for hyperphosphaturia and possible absorptive hypercalciuria type Ill (renal phosphate leak hypercalciuria); verity the diagnosis by determining the vitamin D3 level or with a clinical tial of orthophosphate therapy + Start a therapeutic trial of dietary modification treatment hitpssfemeckcine.medscape.comiatiler2182757-print 151029730122, 254 PM hips femedicine medscape.comlaricle!2182757-print ‘+ Repeat the blood and 24-hour urine tests + Ifthe hypercalciuria is controlled successfully with dietary modification, continue the therapy and repeat testing periodically; if dietary modification is unsuccessful, consider a trial of thiazide therapy ‘+ Orthophosphates are typically recommended if thiazides are not tolerated well or fail to control urinary calcium levels adequately; they are particularly useful in hypercalciuric patients with elevated vitamin-D levels; patients whose hypercalciuria fails all of these therapies require further evaluation @medicine Urinalysis ‘A.urinary tract infection is suggested by the presence of leukocyte esterase, white blood cells (WBCs), nitrite, or bacteria on microscopic examination findings. A urinalysis also can identify hematuria, a common, but insensitive and nonspecific, finding in children with hypercalciuria, ‘The urinary pH and the presence of crystals also may help to identify possible clues or an explanation of the observed symptoms, Uric acid and calcium oxalate crystals are usually seen in acidic urine, whereas calcium phosphate and carbonate crystals are usually seen in alkaline urine. Similarly to hematuria, however, the presence of crystals or an abnormal pH is neither sensitive nor specific for hypercalciuria, Urinary calcium, creatinine, and uric acid Not only does this study function as a reasonable screening test to document hypercalciuria, it also reveals hyperuricosuria, ‘The calciumicreatinine and uric acid/ereatinine ratios should be calculated to determine whether or not abnormalities are present, The normal calcium/ereatinine ratio is less than 0.2; ifthe calculated ratio is higher than 0.2, repeat testing is indicated. If the follow-up results are normal, then no additional testing for hypercalciuria is needed. On the other hand, if the ratio remains elevated, a timed 24-hour urine collection should be obtained and the calcium excretion calculated. ‘The 24-hour calcium excretion test is the criterion standard for the diagnosis of hypercalciuria. f the calcium excretion is higher than 4 mg/kg/day, the diagnosis of hypercalciuria is confirmed and further evaluation is warranted. Similarly, if hyperuricosuria is detected (through the uric acid_to-creatinine ratio), the appropriate evaluation for this condition should be initiated Urinary calcium/osmolality ratio In children with decreased muscle mass, urinary calcium/osmolality ratio has been suggested as a more specific and sensitive screening test than calcium/creatinine ratio because of decreased urinary creatinine excretion in those patients. A urinary calcium/osmolality ratio (X 10) of less than 0.25 is considered to be suggestive of hypercalciuria, Additional studies Freshly voided urine should be measured for bicarbonate and pH. A 24-hour urine collection also should be collected, for measurement of calcium, phosphorus, sodium, and magnesium. medicine 24-Hour U ‘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 litle value when patients are hospitalized with acute stone attacks or other medical problems, since their diet and activity levels are different from the home conditions under which they formed the stones. The 24-hour urine sample should be collected in a standardized fashion, In addition to calcium, other 24-hour urine chemistries that are usually performed in stone formers include the following (if possible, these chemistries should be performed together) Oxalate pH Volume Creatinine Specific gravity Phosphorus or phosphate Citrate Sodium hitpssfemedicine.medscape.comiatiler2182757-print 161429730122, 254 PM hips femedicine medscape.comlaricle!2182757-print + Uric acid + Magnesium + Urea nitrogen or sulfate - These are increased in cases of high protein ingestion Ensure that the laboratory performing the studies has a reliable methodology for urinary chemistry testing. In the United States, this most often requires sending most 24-hour urine tests to an outside reference laboratory. Because usually only a ‘small portion of the total sample is actually sent, some potential errors are introduced if the urine sample is not handled property or if the total volume is not measured and recorded accurately. Instructions for proper 24-hour urine collection procedures must be reviewed carefully with every patient. (The most inteligent patients are often the ones who rush through the instructions and misunderstand, delivering grossly inaccurate specimens.) One easy way to determine the accuracy of urine collection is to compare the total urinary creatinine collected with the expected levels. A properly performed 24-hour urine collection should show a mean urinary creatinine of 22.1 mgjkg in men and 17.2 mgikg in women. Any values that are significantly different from the predicted ones probably represent improper or inaccurate collections. medicine Calcium Loading Test ‘The theoretical advantage of a formal calcium-loading test is a more precise diagnosis, which leads more quickly to definitive therapy. This is particularly useful in differentiating absorptive hypercalciuria type I and type Il from renal leak hypercalciuria, Usually, 2 separate 24-hour urine collections are gathered and analyzed for calcium while the patient is on a regular diet, This is undertaken to confirm the diagnosis of hypercalciuria, establish the baseline urinary calcium level, and determine i the degree of hypercalciuria is consistent and reproducible, ‘The patient is placed on a strict low-calcium diet of 400 mg of calcium and 100 mEq of sodium per day for 1 week. At the end of the week, an additional 24-hour urine sample is taken and tested for calcium and creatinine. Fasting sample ‘The fasting phase begins at 9 pm and continues until 7 am the following morning. The patient voids at 7 am, and the specimen is discarded. He or she is provided with an additional 400-600 mL. of water to drink. For the next 2 hours, the patient continues fasting but does not urinate again until 9 am, when he/she is asked to void. The urine is collected and analyzed for calcium and creatinine. This specimen is called the fasting sample. Post-calcium load sample Next, the patient is administered a 1-9 oral calcium load, which usually consists of an appropriate amount of calcium M Hips femedine macscapa com/arle2182757-pxnt Dipyridamole Dipyridamote (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 D3 and then in reduced hypercalciuria. This is useful in pationts with vitamin D-dependent hypercalciuria, such as the renal phosphate leak (absorptive hypercalciura type Ill) form, 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 rena phosphate leak on a long-term basis.[47, 48] Parathyroid hormone PTH orits amino-terminal fragment has been shown stimulate bone formation and resorption without causing hypercalcemia, 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 [49] ‘The group that received the PTH injections had reductions in fracture rates of 65-86%,[49] Urinary calcium excretion was increased only slightly (roughly by 30 mg of calcium per day in the trealed group), but the overall incidence of hypercalciuria was no different between the PTH-treated group and the patients who received placebo. This most likely was due to the single daily dosing of the PTH, which minimized the hypercalcemic and hypercalciuric responses [49] In short, this is @ 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 holds promise in treating osteoporosis and, possibly, select cases of hypercalciuria medicine Absorptive Hypercalciuria Therapy Absorptive hypercalciuria type | Treatment of absorptive hypercalciuria type | 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 ‘Thiazides, such as trichlormethiazide (Naqua) or indapamide (Lozol), substantially reduce urinary calcium excretion, but they do not correct the primary defect, which is increased, uncontrolled intestinal calcium absorption. Thiazides may lose their hypocalciuric effect over time and cause hypokalemia, hypocitraturia, and increased uric acid levels. Orthophosphates COrthophosphates, such as K-Phos Neutral, Neutra-Phos K, and Uro-KP-Neutral, lower serum vitamin D3 levels and reduce urinary calcium excretion. These agents are roughly equal to thiazides in their abilty 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 | Sodium cellulose phosphate Sodium cellulose phosphate is an extremely potent intestinal calcium-binding agent that was previously recommended as a primary therapy for absorptive hypercalciuria type I. 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 therapy is used, supplemental magnesium is 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 to avoid magnesium depletion Oxalate Dietary oxalate restriction is also recommended, due to the lack of free intestinal calcium that is created with 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, hitpssfemeckcine.medscape.comiatiler2182757-print 201029730122, 254 PM hips femedicine medscape.comlaricle!2182757-print Additional treatments 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 to reduce urinary calcium levels. Optimization of all other urinary stone risk factors is highly recommended. This would include increasing urinary volume, reducing dietary oxalate, and using potassium citrate as needed. Purine intake should be restricted if uric acid levels are elevated Pentosan polysulphate (Elmiron) may potentially have use in difficult calcium oxalate stone cases. Although it has no effect specifically on calcium excretion, pentosan polysulphate appears to reduce calcium oxalate crystalization and crystal aggregation, which reduces new kidney stone formation rates.(50, 51, 52] Absorptive hypercalciuria type Il ‘Treatment is generally with dietary modifications, whenever possible, including restriction to a moderate calcium intake. Overly strict dietary calcium reductions are discouraged, however, because of the possibilty of creating a negative calcium balance and osteoporosis. Moreover, dietary calcium reduction causes a lack of oxalate-binding sites in the intestinal tract, increasing urinary oxalate levels and potentially negating the benefit of urinary calcium reductions. If patients decide that they cannot follow the recommended calcium diet or if the dietary changes are ineffective, ‘orthophosphate 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 problem occurs, it generally arises at least 2 years after treatment initiation. A period of altemate therapy, such as treatment with 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 Ill Because the specific renal defect cannot be corrected in this condition, which is also known as renal phosphate leak hypercalcemia, the most effective treatment is oral orthophosphate therapy. This corrects the hypophosphatemia and limits the amount of vitamin D3 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 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 [47] @medicine Renal Leak Hypercalciuria Therapy ‘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 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; 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/day and indapamide (Lozol) 1.25-2.5 mgiday. ‘These 2 medications can be administered just once a day and tend to carry fewer adverse effects than do 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, medicine Resorptive Hypercalciuria and Hyperparathyroidism Therapy ‘The recommended treatment for patients with hyperparathyroidism who produce calcium stones is parathyroid surgery. For individuals 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 hitpssfemecicine.medscape.comiatile’2182757-print 30142