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Hypercalciuria is a medical term for excessive urinary calcium excretion and is generally considered to be the most common identifiable metabolic risk factor for calcium kidney stone disease (calcium nephrolithiasis). Hypercalciuria also contributes to osteopenia and osteoporosis. Its significance is primarily due to these two clinical entities: nephrolithiasis (kidney stone disease) and bone resorption. On average, hypercalciuric calcium stone formers have decreased bone mineral density than matched controls which are neither stone formers nor hypercalciuric. Even among kidney stone patients, those with hypercalciuria will have average bone calcium density measurements 5% to 15% lower than their normocalciuric peers. Cortical bone is more affected by hypercalciuria than cortical bone. Interestingly, bone mineral density is inversely related with hypercalciuria in nephrolithiasis patients but not in patients without nephrolithiasis.
The definition of hypercalciuria can be a bit confusing. Traditionally, it has been defined as daily urinary calcium excretion of greater than 275 mg in men and greater than 250 mg in women. This definition ignores concentration, age, renal function, and weight considerations as well as the obvious question of whether a different normal excretion amount is reasonable based solely on gender.
Hypercalciuria also can be defined as a daily urinary excretion of more than 4 mg calcium/kg body weight. This definition is somewhat more useful in the pediatric age group if the child is over two years old; but in adults, it tends to allow higher urinary calcium excretions in heavier and obese individuals compared to lighter patients. One solution is to use 24-hour urinary calcium concentration (less than 200 mg calcium/liter urine is normal” but less than 125 mg calcium/liter is optimal).
Another clinically useful definition, especially in pediatrics, is the random or spot urinary calcium/creatinine ratio (less than 0.2 mg calcium/creatinine mg is normal while less than 0.18 mg calcium/creatinine mg is optimal). Its benefit is that it does not necessarily need a 24-hour urine collection with every visit just to track hypercalciuria.
Which definition to use depends on the clinical situation and the availability of reliable 24-hour urine collection data. For optimal results, one approach is to look at all of the definitions and concentrate treatment on optimizing the worst of them. This “optimization” approach focuses less on what is normal and more on what an optimal level would be for a calcium stone forming patient. This type of optimization also can be used for other urinary chemical risk factors besides hypercalciuria.
Young children and infants tend to have higher urinary calcium excretion and lower urinary creatinine levels, so the suggested normal limits for calcium/creatinine ratios differ by age as follows:
- • Up to six months of age: less than 0.8
- • Six to twelve months of age: less than 0.6
- • 24 months and older: less than 0.2
In children 2-12 years of age, the calcium/citrate ratio has been found to be useful clinically. A cutoff of 0.25 has been suggested meaning that those with a calcium/citrate ratio >0.25 are more likely to develop stones.
Hypercalciuria occurs in 5% to 10% of the adult population and is found in about one-third of all calcium stone formers. Close relatives of hypercalciuric patients tend to have an increased rate of hypercalciuria themselves. Up to 40% of the first and second-degree relatives of hypercalciuric recurrent stone formers will also have hypercalciuria.
There are more than 30 million kidney stone patients and 1.2 million new kidney stone cases every year in the United States with one-third of them demonstrating hypercalciuria when tested.
Post menopausal women with osteoporosis and no history of kidney stones have a 20% chance of having hypercalciuria.
In children, both the incidence and prevalence of urolithiasis is increasing, particularly over the last 10 to 15 years. Hypercalciuria and hypocitraturia are the most commonly found metabolic problems identified in pediatric stone formers. The most common stone composition in children is calcium oxalate and calcium phosphate, but there is no apparent association between nephrolithiasis and obesity in the pediatric age group while there is such a linkage in adult stone formers. There also appears to be a higher incidence of hypercalciuria and hyperuricosuria in children with significant vesicoureteral reflux (VUR) compared to controls.
A recent study has connected hypercalciuric pediatric kidney stone patients with an increase in their urinary excretion of lipid metabolism/transport-related proteins. This suggests that abnormalities in lipid metabolism may be responsible or connected in some way to pediatric hypercalciuria and nephrolithiasis.
Hypercalciuria causes
The traditional way of looking at hypercalciuria includes absorptive which has increased intestinal calcium absorption, renal calcium leak which is an inherent kidney problem, resorptive as in hyperparathyroidism, and renal phosphate leak hypercalciuria. Not every patient will fall nicely into one of these categories, and a simpler classification requiring much less testing is now available based on clinical response.
Hypercalciuria without any obvious cause, which is the majority of cases, is called idiopathic. 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. Idiopathic hypercalciuria is diagnosed when clinical, laboratory, and radiographic investigations fail 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 secondary hypercalciuria:
- Absorptive hypercalciuria. Absorptive hypercalciuria is the most common type of excessive urinary calcium excretion. It is found in about 50% of all calcium stone forming patients. Increased gastrointestinal calcium absorption increases serum calcium levels while lowering serum Vitamin D and parathyroid hormone levels. Only about 20% of ingested calcium is absorbed, normally taking place in the duodenum. A Vitamin D dependent version of absorptive hypercalciuria can be identified by high serum Vitamin D levels.
- Renal phosphate leak hypercalciuria (also known as absorptive hypercalciuria type 3). Renal phosphate leak hypercalciuria is perhaps the most interesting from a pathophysiological point of view. A renal defect causes excessive urinary phosphate excretion which leads to hypophosphatemia. This induces higher Vitamin D activation in the kidney which increases intestinal phosphate absorption to correct the low serum phosphate. Unfortunately, the extra Vitamin D also increases intestinal calcium absorption. The extra calcium absorbed is eventually excreted in the urine resulting in hypercalciuria. This type of hypercalciuria is Vitamin D dependent and is relatively unresponsive to thiazides. The diagnosis is made by the findings of low or low-normal serum phosphate, hypercalciuria, high urinary phosphate, and high serum Vitamin D3 levels with normal serum calcium and parathyroid hormone (PTH) levels.
- Renal leak hypercalciuria. Renal calcium leak is found in about 5% to 10% of hypercalciuric stone formers. It is caused by a renal defect that causes an obligatory loss of calcium in the urine regardless of serum calcium levels or dietary calcium intake. This is usually accompanied by hypocalcemia and an increase in serum parathyroid hormone (PTH) levels. The calcium/creatinine ratio tends to be high in this condition (usually greater than 0.20), and there is an association with Medullary Sponge Kidney.
- Resorptive hypercalciuria – This is almost always caused by hyperparathyroidism. Resorptive hypercalciuria accounts for only about 3% to 5% of all hypercalciuric patients and is almost always due to hyperparathyroidism. Sustained, inappropriate, and excessive serum parathyroid hormone causes a release of calcium from the bone leading to osteopenia and hypercalcemia. Eventually, the hypercalcemia overcomes the normal parathyroid hormone effect of decreasing urinary calcium excretion, and the result is hypercalciuria (e.g., similar to spilling sugar in the urine in diabetics). This explains why hypercalciuria from hypercalcemia is less for any given elevated serum calcium level in patients with hyperparathyroidism than in other patients who are hypercalcemic.
Other causes of secondary hypercalciuria that need to be considered include the following:
- • Hyperthyroidism
- • Milk-alkali syndrome (excessive oral calcium ingestion)
- • Renal tubular acidosis
- • Sarcoidosis and other granulomatous diseases
- • Vitamin D intoxication
- • Glucocorticoid excess
- • Paget disease
- • Addison disease
- • Albright tubular acidosis
- • Various paraneoplastic syndromes
- • Prolonged immobilization
- • Induced hypophosphatemic states
- • Multiple myeloma
- • Lymphoma
- • Leukemia
- • Metastatic tumors (especially to the bone)
Pregnancy increases hypercalciuria during all three trimesters, but this does not appear to increase the risk of new stone disease as there is also an increase in kidney stone inhibitors.
High salt (sodium) intake has also been suggested as a possible cause of hypercalciuria. An increased sodium load leads to higher urinary excretion of sodium which decreases tubular calcium reabsorption resulting in hypercalciuria. While high salt intake may be a contributing factor, it is rarely the sole cause of significant hypercalciuria.
Many other dietary factors can alter urinary calcium excretion, including the following:
- • Protein
- • Glucose
- • Sucrose
- • Magnesium
- • Phosphate
An inverse relationship between phosphate intake and urinary calcium excretion is observed; thus, phosphate-restricted diets result in an increase in urinary calcium excretion. With all of the other dietary items mentioned above, a direct relationship between dietary intake and urinary calcium excretion is observed.
A high animal protein diet will produce an acid load that causes a release of calcium from the bone and inhibition of renal tubular calcium reabsorption resulting in hypercalciuria. Again, this does not appear to be the sole causes of significant hypercalciuria.
Certain medications, such as vitamin-D supplements and furosemide, may contribute to hypercalciuria. All loop diuretics decrease the tubular reabsorption of calcium.
Dent disease. Dent disease is a rare, X-linked hereditary disorder that primarily affects the proximal renal tubules resulting in hypercalciuria and proteinuria starting in childhood. It may progress from there, leading to osteomalacia, short stature, nephrocalcinosis, nephrolithiasis, hypophosphatemia and eventually renal failure. Up to 80% of affected males will develop end-stage renal failure by age 50. Vitamin D levels (1,25 (OH)2 Vit. D) are elevated or in the high normal range while parathyroid hormone levels are low. There are only about 250 families known to carry this disorder, so the incidence is quite low. Treatment is based on controlling hypercalciuria and preserving renal function. While this can be done with thiazide diuretics, the hypercalciuria almost always responds to dietary therapy. ACE inhibitors and citrate supplements are used in children with the disorder to help preserve renal function, but their effectiveness is unclear.
Wong and colleagues reported that hypercalciuria was present in 91.9% of subjects on deferasirox, an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies but was not present in a control group taking an alternative iron chelator, deferoxamine.
Mahyar et al reported a significantly higher frequency of hypercalciuria and hyperuricosuria in children with vesicoureteral reflux (VUR) than in a control group. These authors also observed a positive correlation between hypercalciuria and hyperuricosuria and severity of vesicoureteral reflux.
Animal studies have suggested that in some subjects, there appears to be an increased sensitivity to Vitamin D. This may be due to an increased number of 1,25 Vitamin D receptors in those individuals. These changes have not been reliably identified in humans; just in animal studies.
Hypercalciuria symptoms
There is no specific clinical finding of hypercalciuria itself, but it should be suspected in cases of calcium nephrolithiasis, nephrocalcinosis, hypercalcemia, hyperparathyroidism and osteopenia/osteoporosis. Hypercalciuria also can cause hematuria even without any detectable stone formation, particularly in children. The cause is thought to be from focal and microscopic tissue damage from tiny calcium crystals and focal stones that are too small to be diagnosed with standard techniques. Urinary testing makes the definitive diagnosis.
In children, hypercalciuria is often associated with some degree of hematuria and back or abdominal pain, and is also sometimes associated with voiding symptoms. The standard treatment for pediatric hypercalciuria is limited to dietary or short-term medical therapy, because the patients become asymptomatic when the hypercalciuria is corrected and are often lost to follow-up.
A study involving 124 children with idiopathic hypercalciuria found that 50% of these patients had a family history of kidney stone disease. Fifty-two children developed clinical symptoms of flank or abdominal pain during the study period, but only 6 of these children had actual renal calculi. Twenty-seven children had hematuria, and 10 had incontinence. The children were treated with increased fluid intake and a reduction in dietary oxalate and sodium. Some required treatment with thiazides. All but 5 of the patients responded to therapy. Resolution of the hypercalciuria eliminated the recurrent pain in this patient population.
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. Because limiting calcium intake in children is unwise, the recommended dietary therapy for hypercalciuria is to use a low-sodium/high-potassium diet, which normalizes the hypercalciuria in most pediatric patients.
In children with hypercalciuria, microcrystallization of calcium with urinary anions has been suggested to lead to injury of the uroepithelium. Consequently, when taking the history of the illness, attempt to identify symptoms relating to the urinary tract. Pay particular attention to the following signs and symptoms:
- • Dysuria
- • Abdominal pain
- • Irritability (infants)
- • Urinary frequency
- • Urinary urgency
- • Change of urinary appearance
- • Colic
- • Daytime incontinence
- • Isolated or recurrent urinary tract infections
- • Vesicourethral reflux
Some clinical manifestations are age dependent. For instance, irritability may be the only manifestation in infants, but a teenager may experience renal colic and hematuria.
Hypercalciuria diagnosis
The 24-hour calcium excretion test is the criterion standard for the diagnosis of hypercalciuria. If the calcium excretion is higher than 4 mg/kg/day, the diagnosis of hypercalciuria is confirmed and further evaluation is warranted. In clinical practice, a 24-hour urinary calcium level of 250 mg is a useful initial threshold for determining hypercalciuria. In pediatrics, a ratio of more than 4 mg calcium/kg body weight, a random calcium/creatinine ratio of more than 0.18, or a 24-hour urinary calcium concentration of more than 200 mg/liter may be more useful. In practice, it often is used to identify whichever method gives the most abnormal reading and try to “optimize” it.
Spot urinary chemistry has shown poor sensitivity and specificity for hypercalciuria which is why the 24 hour urine test is so critical in making the diagnosis.
The calcium/creatinine and uric acid/creatinine ratios should be calculated to determine whether or not abnormalities are present. The normal calcium/creatinine ratio is less than 0.2; if the calculated ratio is higher than 0.2, repeat testing is indicated. If the follow-up results are normal, then no additional testing for hypercalciuria is needed. On the other hand, if the ratio remains elevated, a timed 24-hour urine collection should be obtained and the calcium excretion calculated.
Hyperparathyroidism should be suspected in all adult hypercalciuric patients with elevated or borderline elevated serum calcium levels. It can be diagnosed simply by checking a parathyroid hormone level in those individuals.
Vitamin D levels can help detect Renal Phosphate Leak (where vitamin D is elevated along with high urinary but low serum phosphate levels). High vitamin D levels and possible Renal Phosphate Leak should be suspected in patients who do not respond to adequate thiazide therapy.