Hypercalciuria is generally considered to be the most common identifiable metabolic risk factor for calcium nephrolithiasis. It also contributes to osteopenia and osteoporosis. Its significance is primarily due to these two clinical entities: nephrolithiasis 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.
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:
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.
Other causes of hypercalciuria include milk-alkali syndrome (excessive oral calcium ingestion), sarcoidosis, glucocorticoid excess, Paget disease, paraneoplastic syndrome, multiple myeloma, metastatic tumors involving bone, Addison disease, and Hypervitaminosis D. Hypercalciuria without any obvious cause, which is the majority of cases, is called idiopathic.
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.
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.
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.
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 meanting 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 compared to controls.
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 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 PTH levels.
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 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.
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.
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.
In children, there is an apparent connection between recurrent abdominal pain and hypercalciuria. 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.
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 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.
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.
If serum calcium levels are normal (which rules out hyperparathyroidism), dietary calcium is moderated if excessive but is not overly restricted to avoid increased oxalate absorption and bone demineralization. A diet that is low in animal protein and salt (sodium) is recommended. Then, a repeat 24-hour urine test can be done to determine the response. If hypercalciuria persists, then medication (such as thiazides) likely will be needed. If thiazides fail, even after adjusting the dose and moderating sodium intake (which negates the hypocalciuric effect of the thiazides), then the patient could have renal phosphate leak hypercalciuria which does not typically respond to thiazide-type medications.
Thiazides can induce a positive calcium balance and reduce urinary calcium by up to 50%. Hydrochlorothiazide and chlorthalidone are used most often, but indapamide also can be used. The advantage of chlorthalidone and indapamide is their longer half-life as hydrochlorothiazide would need to be given twice a day. Thiazides will not be effective unless dietary salt intake is limited. For every gram of daily dietary salt decrease, 24 hour urinary calcium would be expected to drop by 5.46 mg.
Thiazides will also tend to reduce serum potassium, increase uric acid levels, and lower urinary citrate excretion. For that reason, it often is useful to add potassium citrate to these patients when they start on thiazide therapy.
When thiazides fail even at adequate dosages in patients with reasonable sodium restriction, it could be due to a Vitamin D-dependent form of hypercalciuria such as Renal Phosphate Leak. This variant can be treated with orthophosphates, which generally lower serum Vitamin D, or with ketoconazole which blocks cytochrome P450 3A4 resulting in a 30% to 40% reduction in circulating Vitamin D3 levels.
Orthophosphate therapy not only increases serum phosphate levels, which naturally lower Vitamin D3 activation, but also increases renal calcium reabsorption and urinary stone inhibitors like pyrophosphate. They also may act as gastrointestinal calcium binders to help reduce absorption. Orthophosphates can reduce urinary calcium excretion by up to 50% and may be given together with thiazides when necessary. However, they are most useful in cases where thiazides have failed or cannot be used as well as for renal phosphate leak hypercalciuria.
Amiloride, a potassium-sparing diuretic, is not a thiazide but when added to thiazides may further increase calcium reabsorption as well as minimizing potassium loss. (Amiloride is not usually recommended with potassium citrate due to the potential for hyperkalemia.) Triamterene is not recommended in stone formers as it can form triamterene calculi.
Potassium citrate therapy will not only increase urinary citrate levels, but it may also increase renal calcium reabsorption reducing hypercalciuria.
In children, treatment of hypercalciuria is primarily dietary, at least initially. Calcium intake should not be restricted unless it exceeds the usual recommended amount. Vitamin D supplementation should be avoided, and dietary animal protein intake should be limited to within the usually recommended limits. A 3 to 6 month trial of dietary measures alone is reasonable before resorting to thiazide medications.
Treatment Summary for Idiopathic HypercalciuriaFirst try dietary modifications, such as avoiding excessive dietary calcium intake and lowering dietary animal protein and salt. If this is not successful, initiate thiazide therapy and maintain a low salt diet. If this is also ineffective, start orthophosphate therapy. Additional medications that can help control hypercalciuria include amiloride and potassium citrate.
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.
Hypercalciuria can be difficult to identify and manage. Diagnosis usually begins with primary care, nephrology or urology. It can take time to identify the type of hypercalciuria and its optimal treatment. A high index of suspicion should be maintained by all members of the health care team treating the patient.
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