Hypercalciuria

Etiology

Most of the serum calcium filtered by the glomerulus (>60%) is reabsorbed in the proximal tubule. This is accomplished by a paracellular pathway involving tight junction proteins called claudins which contribute to the ion selectivity of these pathways. This process is driven by water and particularly sodium reabsorption. About 30% to 35% of the remaining calcium is reabsorbed in the thick ascending limb of the loop of Henle using different claudin proteins. Activated vitamin D (1,25-dihydroxy vitamin D3) downregulates claudin activity. Claudins are also paracellular pathways for magnesium, and upregulation can be stimulated by hypomagnesemia.[7] 

The distal convoluted tubule and the collecting ducts regulate the remaining calcium excretion and reabsorption utilizing several chemical pathways. Typical idiopathic hypercalciuria is generally due to a genetic mutation or modification in one of these calcium reabsorption pathways.[8]

The traditional way of looking at hypercalciuria includes the following:

• Absorptive, which is increased intestinal calcium absorption.
• Renal calcium leak, which is an inherent kidney problem.
• Resorptive, as in hyperparathyroidism.
• Renal phosphate leak hypercalciuria, also a renal defect.[9]

Not every patient will fall nearly into one of these categories as there are overlapping mechanisms.

Other causes of hypercalciuria include:

• Addison disease
• Dent disease
• Familial hypomagnesemia with hypocalciuria and nephrocalcinosis (claudin gene mutations)
• Familial hypophosphatemic hypercalciuric rickets
• Glucocorticoid excess
• Hyperthyroidism
• Hypervitaminosis D
• Metastatic tumors involving bone
• Milk-alkali syndrome (excessive oral calcium ingestion)
• Multiple myeloma
• Paget disease
• Paraneoplastic syndromes
• Renal tubular acidosis
• Sarcoidosis and other granulomatous disorders
• Idiopathic (which constitutes the majority of cases) [10]

Animal studies have demonstrated an increased sensitivity to vitamin D. This may be due to more 1,25 vitamin D receptors in those individuals. These changes have not yet been reliably identified in humans.[11]

High sodium intake has also been suggested as a possible cause of hypercalciuria.  An increased sodium load leads to higher urinary excretion, decreasing tubular calcium reabsorption and resulting in hypercalciuria. While high salt intake may be a contributing factor, it is rarely the sole cause of significant hypercalciuria.[4]

A high animal protein diet will produce an acid load that causes release of calcium from the bones and inhibits renal tubular calcium reabsorption, resulting in hypercalciuria. Again, this is not usually the sole cause of significant hypercalciuria.[12]

In children 2 to 12 years of age, the calcium/citrate ratio has been found to be clinically useful. A cutoff of 0.25 has been suggested, meaning that those with a calcium/citrate ratio >0.25 are more likely to develop stones.[3][6] Vesicoureteral reflux has also been positively linked with hypercalciuria in the pediatric age group.[13]

Epidemiology

Hypercalciuria occurs in 5% to 10% of adults 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 patients with hypercalciuria and recurrent stones will also have hypercalciuria.[14]

There are more than 30 million patients with kidney stones and 1.2 million new kidney stone cases every year in the United States, with one-third demonstrating hypercalciuria when tested. In patients with recurrent kidney stones, the prevalence of idiopathic hypercalciuria is 40% to 50%.[15]

Postmenopausal women with osteoporosis and no history of kidney stones have a 20% chance of having hypercalciuria. Calcium phosphate stones are much more common in women than in men.[1] In addition, up to 40% of post-menopausal women with osteoporotic fractures and no history of kidney stones were found to have hypercalciuria.[15]

In children, the incidence and prevalence of urolithiasis are increasing, particularly over the last 10 to 15 years. Hypercalciuria and hypocitraturia are the most commonly found metabolic problems identified in pediatric patients with nephrolithiasis. The most common stone compositions in children are calcium oxalate and calcium phosphate. There is no apparent association between nephrolithiasis and obesity in the pediatric age group, while there is such a linkage in adult patients with kidney stones. There also appears to be a higher incidence of hypercalciuria (and hyperuricosuria) in children with significant vesicoureteral reflux compared to controls.[3][6]

Pathophysiology

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 (PTH) 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 relatively high serum vitamin D levels.[3]

Renal calcium leak hypercalciuria is found in about 5% to 10% of all 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 increased serum 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.[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, increasing 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.

Renal phosphate leak hypercalciuria is vitamin D-dependent and 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.[3] 

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 bones, leading to osteopenia and hypercalcemia. Eventually, the hypercalcemia overcomes the usual PTH effect of decreasing urinary calcium excretion, which results in hypercalciuria (eg, similar to spilling sugar in the urine of diabetics). This explains why hypercalciuria from hypercalcemia is less for any given elevated serum calcium level in patients with hyperparathyroidism than in other hypercalcemic patients.[3]

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. 

Metabolic acidosis can cause hypercalciuria from its direct effect on renal tubular cells. The mechanism is decreased calcium reabsorption from the renal tubules. This effect is unrelated to vitamin D or PTH activity.[16]

Trabecular bone is more affected by hypercalciuria than cortical bone. Interestingly, bone mineral density is inversely related to hypercalciuria in nephrolithiasis patients with nephrolithiasis but not those without.[15]

In children, there is an apparent connection between recurrent abdominal pain and hypercalciuria. A recent study has connected hypercalciuric pediatric kidney stone patients with increased 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.[3][6]

Rare Causes

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 vitamin D) are elevated or in the high normal range, while PTH levels are low. There are only about 250 families known to carry this disorder, so the incidence is extremely low.[17]

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.[17]

Familial (hereditary) hypophosphatemic hypercalciuric rickets is a rare autosomal genetic cause of severe renal phosphate leak hypercalciuria with an incidence of 1:250,000.[18] Unlike the more common X-linked hypophosphatemia, this disorder is associated with elevated vitamin D levels and hypercalciuria; about half of those affected will have nephrocalcinosis or nephrolithiasis.[18] Treatment is oral orthophosphates.[18] Vitamin D supplementation is contraindicated. Burosumab, a monoclonal antibody FDA-approved for X-linked hypophosphatemia, is not indicated or helpful.

Histopathology

Patients with calcium oxalate stones usually have white deposits in the renal papillae called Randall's plaques which serve as a nidus for stone formation. Biopsy of these plaques shows interstitial calcium phosphate deposits which originate in the basement membrane of the thin segment of the Loop of Henle. These can become niduses for the deposit of protein, minerals, and calcium oxalate (despite the initial deposit being calcium phosphate). Patients who form calcium phosphate stones may also have Randall's plaques but primarily have calcium phosphate deposits in the collecting tubules, from which stones form.[19]

History and Physical

There is no specific clinical finding of hypercalciuria in adults, but it should be suspected in cases of calcium nephrolithiasis, nephrocalcinosis, hypercalcemia, hyperparathyroidism, urinary crystalluria, and osteopenia/osteoporosis. 

Hypercalciuria can cause hematuria even without detectable stone formation, particularly in children. The cause is thought to be focal and microscopic tissue damage from tiny calcium oxalate crystals and focal stones too small to be diagnosed with standard techniques.

Children are generally more symptomatic than adults, and pediatricians must have high suspicion to detect hypercalciuria. Children may have gross or microscopic hematuria, urinary urgency, dysuria, enuresis, incontinence, and suprapubic and urethral pain. They may also demonstrate abdominal or flank pain without nephrolithiasis.[20] 

Evaluation

Diagnosing hypercalciuria first requires a 24-hour urine collection testing for calcium content. This continues to be the standard recommended practice for all pediatric patients with kidney stones, high-risk adults with nephrolithiasis (such as solitary kidney, renal failure, renal transplant, ureteral reimplant), patients with recurrent nephrolithiasis, and any highly motivated patient who would like to avoid recurrent kidney stones.[21] Spot urinary chemistry has shown poor sensitivity and specificity for hypercalciuria which is why the 24-hour urine test is critical in diagnosis.[4] 

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 helpful. In practice, whichever method gives the most abnormal reading may be used, and treatment response can be adjusted to  "optimize" this number.[3]

Hyperparathyroidism should be suspected in all adult hypercalciuric patients with elevated or borderline elevated serum calcium levels. It can be diagnosed simply by checking the PTH level in those individuals.[22]

Checking 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 hypercalciuria should be suspected in patients who do not respond to adequate thiazide therapy.[23]

Treatment / Management

If serum calcium levels are normal (which rules out hyperparathyroidism), dietary calcium should be moderated if excessive but not overly restricted to avoid increased oxalate absorption and bone demineralization. A diet low in animal protein and sodium is recommended. Then, a repeat 24-hour urine test can be done to determine the response.[22]  If hypercalciuria persists, medication (such as thiazides) will likely be needed. If thiazides fail, even after adjusting the dose and moderating sodium intake (which negates the hypocalciuric effect of thiazides), then the patient could have renal phosphate leak hypercalciuria, which does not typically respond to thiazide-type medications.[4] In these cases, oral orthophosphates are the recommended treatment.

Thiazides can induce a positive calcium balance and reduce urinary calcium by up to 50%. This effect is due to the increased renal calcium tubular reabsorption in exchange for excretion of sodium and water.[24] 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 optimally 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.[4][25]

Thiazides will also reduce serum potassium, increase uric acid levels, and lower urinary citrate excretion. Therefore, it is often necessary to add potassium citrate to these patients when thiazide therapy is started.[3](B2)

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 lower serum vitamin D) or with ketoconazole (which blocks cytochrome P450 3A4 resulting in a 30% to 40% reduction in circulating vitamin D3 levels).[3](B2)

Orthophosphates increase serum phosphate levels, naturally lowering vitamin D3 activation, while increasing 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, such as for renal phosphate leak hypercalciuria.[4][26](B3)

Amiloride, a potassium-sparing diuretic, may further increase calcium reabsorption and minimize potassium loss when added to thiazides. Amiloride is not usually recommended with potassium citrate due to the potential for hyperkalemia.[27] Triamterene is not recommended in patients prone to nephrolithiasis, as it can form triamterene calculi.[25]

Potassium citrate therapy will not only increase urinary citrate levels, but may also increase renal calcium reabsorption, reducing hypercalciuria.[28][29](A1)

Hyperparathyroidism is optimally treated with parathyroid surgery, but calcimimetic agents may also be used if surgery cannot be performed. See our companion StatPearls reference article on "Primary Hyperparathyroidism" for further information.[30]

In children, treatment of hypercalciuria is primarily dietary, at least initially. Calcium intake should not be restricted unless intake exceeds the recommended daily amount. Vitamin D supplementation should be avoided, and dietary animal protein intake should be limited to within the recommended daily limits. A three- to six-month trial of dietary measures alone is reasonable before resorting to thiazide medications.[6][28]

Differential Diagnosis

Hypercalciuria may be caused by disease states not discussed above. Some of these disorders are sarcoidosis, PTH-related peptide production, malignancy, non-calcium based kidney stones (such those composed of uric acid or cystine), or exogenous vitamin D consumption.

Prognosis

Bone health is established in childhood so pediatric hypercalciuria causing decreased bone mass can cause lifelong disease. Peak bone mass is usually achieved by age 20, but it is not clear if decreased bone mass in children leads to adult osteopenia or osteoporosis.[20] Prognosis depends on the underlying etiology, and morbidity is often related to nephrolithiasis and bone fractures from osteoporosis.