Idiopathic hypercalcinuria

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Idiopathic hypercalcinuria (IH) is a condition including an excessive urinary calcium level with a normal blood calcium level resulting from no underlying cause. [1] IH has become the most common cause of hypercalciuria and is the most serious metabolic risk factor for developing nephrolithiasis. [1] IH can predispose individuals to osteopenia or osteoporosis, [2] and affects the entire body. IH arises due to faulty calcium homeostasis, a closely monitored process, where slight deviations in calcium transport in the intestines, blood, and bone can lead to excessive calcium excretion, bone mineral density loss, or kidney stone formation. [1] 50%-60% of nephrolithiasis patients suffer from IH and have 5%-15% lower bone density than those who do not. [3]

Contents

Anatomy of the male urinary system. UrinarySystemMale.jpg
Anatomy of the male urinary system.

The standard definition of hypercalciuria is varied. Hodkinson and Pyrah proposed hypercalciuria as a calcium excretion of over 7.5 mmol in men and 6.25 mmol in women, every 24 hours, [4] but some argue that these values are too restrictive and ignore age, weight considerations, and renal function. Calcium excretion is negatively associated with age until the ages of 30–60, where calcium excretion starts increasing. Calcium excretion begins decreasing following age 60. [4] Other suggested IH be considered a daily urinary excretion of >4 mg of calcium per kg of body weight, [3] making it more applicable among different age groups and weight classes.

IH shares many similarities with hyperparathyroidism, a condition associated with the elevated release of parathyroid hormone from the parathyroid gland. [5] The only discernable feature between the two is the normal blood calcium level associated with IH.

Anatomy of the female urinary system. Urinary System (Female).png
Anatomy of the female urinary system.

Signs and symptoms

IH can be presented with many urinary associated signs and symptoms mostly seen in children. [6] [7] They include: 

Causes

It has been hypothesized that three mechanisms contribute to IH: increased calcium absorption in the intestines, faulty renal tubule calcium reabsorption in the kidneys, and an increased rate of bone resorption. [8] Others estimate IH may arise due to excessive expression of vitamin D receptors. (VDR) or a deficiency in enzymes within the renal tubules. [8]  

Increased intestinal calcium absorption 

A study found that patients with IH have a rate of calcium absorption two times that of healthy individuals, and have elevated levels of calcitriol. [8] Calcium is absorbed through intestinal walls, majorly in the duodenum and to a lower degree in the small intestines and the colon, via two transport systems, a vitamin dependent mechanism and a vitamin independent mechanism. [9] Within the vitamin-dependent mechanism, 1, 25 Dihydroxyvitamin D is responsible for increasing intestinal calcium absorption, which was found elevated in certain IH patients, yet remained normal in others, suggesting other factors resulted in the increased calcium absorption. [8] The increased expression of VDR in the intestinal walls may result in this. [8]  

A diagram of the renal tubules beginning with the glomerulus, then the proximal tubules, the loop of Henle, the distal tubules and the collecting duct. Kirkes' handbook of physiology (1907) (14766693461).jpg
A diagram of the renal tubules beginning with the glomerulus, then the proximal tubules, the loop of Henle, the distal tubules and the collecting duct.

Faulty renal tubule calcium reabsorption

The renal tubules are an important factor in the reabsorption of substances, including glucose, sodium, chloride, and calcium. The renal tubules consist of the proximal tubule, the loop of Henle, the distal tubule and the collecting duct. The glomerulus lies ahead of the renal tubules. Calcium is filtered out of the blood in the glomerulus, and 60% of the calcium is reabsorbed in the proximal tubules, compared to 25% in the loop of Henle, specifically the thick ascending limb. [10] The distal convoluted tubule and the collecting duct monitor the reabsorption of the remaining calcium. Significantly low levels of calcium reabsorption were found in patients with IH, [8] suggesting a modification or defect is present in one of the absorptive pathways used by the renal tubules. This can possibly due to less parathyroid hormone release, a key regulator in maintaining calcium reabsorption, or a renal tubule enzyme deficiency, believed to affect the ascending portion of the loop of Henle and the distal tubule. The exact mechanism remains unknown. [8]  

Increased rate of bone resorption 

It was found that IH patients had lower bone density, suggesting increased bone resorption. [11] Bone resorption involves the breaking down of bone tissue and the transfer of calcium ions into the blood. [12] Bone resorption is carried out by specialized bone cells known as osteoclasts. [12] A surge in osteoclast activity can lead to hypercalciuria, as more bone tissue is broken down, meaning more calcium is released into the blood. Histomorphometry studies failed to discover a significant difference in bone volume in IH patients and only found a lower rate of bone formation, [8] yet this is contradicted in other studies.

The mechanism behind how hypercalciuria causes increased bone resorption is still conflicting. A high animal protein diet causes increased bone resorption and bone loss rate. [8] The high level of calcitriol found in hypercalciuria patients mentioned earlier stimulates higher rates of bone resorption and lowers bone formation. [8] Unrestrained amounts of interleukin-1, TNF-α, and GM-CSF released from monocytes were found in hypercalciuria patients, which are key determinants in bone remodelling efficiency, furthering bone density loss. [8]  

Genetic 

IH has been considered a disorder affected by both environmental and genetic factors and has a heterogeneous pathogenesis. [4] It was also found to differ based on family characteristics, and have a familial distribution. 

It was found that 43% of first-degree relatives and 36% of second-degree relatives of patients with hypercalciuria among nine families had IH. [13] IH is believed to have an autosomal dominant transmission pattern, as it was not correlated with gender and was observed in all generations. [4] Pak et al. and Nicolaidou et al. identified the same pattern. [14] [15] Additionally, different hypercalciuria forms within a family were discovered in Lerolle et al., confirming an autosomal dominant transmission. [16]

Kidney stone fragments formed from calcium oxalate. Kidney stone fragments.png
Kidney stone fragments formed from calcium oxalate.

Risk Factors

Calcium levels in the urine can be affected by multiple systems in the body including the digestive system, endocrine system, and skeletal system, to which faulty mechanisms can lead to possible risk factors for IH. Most IH cases have no one direct cause, and involve a flaw in more than one system. 

One risk factor for IH is excessive vitamin D consumption in the diet or taking medicine which disrupts the calcium regulating mechanisms. Such medications may include furosemide which enhances calcium excreted by urine, [17] corticosteroids which reduce the body's ability to absorb calcium, [18] and methylxanthines which stimulate calcium transportation. [19] An example of a methylxanthine is theophylline. 

Excessive vitamin D intake can lead to an overexpression of vitamin D receptors (VDR) causing an elevated serum level of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or calcitriol. An elevated level of 1,25-dihydroxyvitamin D3 stimulates more absorption of calcium in the intestines. [20]

A diet high in sodium [21] and protein further increases the risk of IH. [22] Excessive protein intake may be associated with an enlarged kidney and the overproduction of calcitriol that acts on calcium absorption, causing more excretion of calcium in the urine. [1]

Insufficient water or fluid intake also acts as a risk factor. Lowered water concentration leads to a higher calcium oxalate and calcium phosphate concentration. [23] This supersaturation process leads to higher calcium level excreted through urine.

Diagnosis

Diagnosis for IH includes differential diagnosis and diagnostic methods. Differential diagnosis is made to exclude conditions possibly contributing to the increased urinary calcium levels, by looking for apparent causes through interviews, physical examinations, and dietary recall.

Diagnostic methods are done to measure protein and calcium levels. Increased levels of protein in the urine, proteinuria, can be measured with a urine dipstick test. Three different tests may be used to measure calcium levels in urine, 24-hour urine tests, blood tests, and genetic tests. Measuring calcium levels can also be done using an oral calcium tolerance test. [24] Ultrasound and CT scans of the urinary tract can be done to diagnose kidney stones or kidney abnormalities as IH often accompanies it.

Urine test

Urine tests are routinely done to analyse the composition of urine for the detection of calcium nephrolithiasis. [3] In urine tests, patients are given a week of restricted calcium diet, and their urine samples are collected for two days to assay calcium in the urine. Urine tests with hypercalciuria should result in a 0.2 mg/mg ratio between calcium and creatinine. If calcium excreted in urine is measured to be lower than 0.07 mmol/kg after 24 hours, diet-dependent hypercalciuria can be deduced, and sodium levels in urine can confirm the result. If the test results come back standard but hypercalciuria continues, the patient can be diagnosed with IH. [8]  

Blood tests

Since children diagnosed with hematuria are generally also tested for hypercalciuria, [25] blood tests in urine are performed to rule out diseases, such as hematuria that may be underlying the cause of hypercalciuria. [26]

Genetic tests

Various genetic studies such as genome-wide linkage analysis can be done to search for the genes contributing to IH. A few genes possibly associated with IH were selected for genetic screening, including VDR, TRPV5, CasR, and NPT2a. [27] IH is also associated with many monogenic disorders, whether or not renal calcification is involved. The most studied disease is Dent's disease, which is attributed to a mutation in CLCN5 or OCRL1 genes. However, IH patients have not been detected to carry the CLCN5 mutation. [28]

Treatment 

Diet intervention

The objective of treating IH is preventing nephrolithiasis or the formation of kidney stones. If blood calcium levels are normal, which can rule out hyperparathyroidism, treatment would begin with adopting a diet of ~800 mg of daily calcium, low salt intake, restricted animal protein intake, and increased net fluid intake. [8] Careful dietary decisions should be taken since a deficient calcium intake diet accompanies the risk of excessive bone loss and can increase the absorption of dietary oxalates, found in many leafy greens and vegetables, which combine with calcium in the intestines, [29] and form oxalate kidney stones. [8] The diet's effectiveness can be determined by repeating a 24-hour urine test.

Co-Diovan (Valsartan and hydrochlorothiazide) used as a pharmacuteical intervention for hypertension in adults by increasing the amount of urine produced. Two boxes and a blister pack of Co-Diovan (Valsartan and hydrochlorothiazide), Singapore - 20150210.jpg
Co-Diovan (Valsartan and hydrochlorothiazide) used as a pharmacuteical intervention for hypertension in adults by increasing the amount of urine produced.

Pharmaceutical intervention

If hypercalciuria persists following dietary intervention, pharmaceutical interventions are used, primarily thiazide diuretics. [8] Thiazide therapy has proven effective in preventing the formation of kidney stones, reducing urinary calcium, and preventing the periodic occurrence of nephrolithiasis. [8] Thiazides lessen urinary citrate excretion and blood potassium levels, making it recommended to prescribe potassium citrate alongside thiazide therapy. [3] A thiazide option includes Hydrochlorothiazide. [2] A study found that hydrochlorothiazide cleared hypercalciuria and increased spine and hip bone density. [2] Another option would be to use chlorthalidone or indapamide. [2]

Pharmaceutical interventions should only be made an option succeeding various months of following diet therapy, and a low sodium diet must be maintained throughout the use of thiazide diuretics. [3] If Thiazide therapy fails even after combining it with an appropriate diet, oral orthophosphates are the final recommended treatment. [3]  

Complications

If left untreated, hypercalciuria can cause the following complications:

Nephrolithiasis

Nephrolithiasis is the medical term employing kidney stone formation. The increased saturation of urine with calcium elevates the rate of stone formation within the kidneys, due to the excess calcium precipitating and forming crystals, which develop into larger stones over time. [23] The stones form in the kidneys and leave the body through the urethra, which can cause tremendous amounts of pain. [23]

The difference in bone composition between normal bone and an osteoporosis affected bone in common locations of osteoporosis in IH patients. Osteoporosis Locations.png
The difference in bone composition between normal bone and an osteoporosis affected bone in common locations of osteoporosis in IH patients.

Osteopenia or Osteoporosis

The increased rate of bone resorption causing higher serum calcium levels could lead to osteopenia, or osteoporosis, where bones are excessively thin to the point they fracture easily. [30] Increased fracture risk was identified in nephrolithiasis patients, yet no data directly condemns hypercalciuria for this discovery. [30] Bone loss is unique to nephroliths patients with IH, proposing it has an unidentified role in the increased bone fragility and fracture risk in these patients. [30]

Recurrent urinary tract infections (UTI)

The high urinary calcium levels in IH impair the function of the uroepithelium within the urinary tract, which acts as our body's defence mechanism against bacteria. It coordinates the inflammatory response and the release of antibodies. [31] The uroepithelium must be in physical contact the bacteria to initiate a defence mechanism, but the calcium-oxalate crystals formed in IH prevent this and prevent the elimination of bacteria by excretion [31] and increases the chance of developing UTIs.

Related Research Articles

<span class="mw-page-title-main">Kidney stone disease</span> Formation of mineral stones in the urinary tract

Kidney stone disease, also known as renal calculus disease, nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material develops in the urinary tract. Renal calculi typically form in the kidney and leave the body in the urine stream. A small calculus may pass without causing symptoms. If a stone grows to more than 5 millimeters, it can cause blockage of the ureter, resulting in sharp and severe pain in the lower back or abdomen. A calculus may also result in blood in the urine, vomiting, or painful urination. About half of people who have had a renal calculus are likely to have another within ten years.

<span class="mw-page-title-main">Calcium metabolism</span> Movement and regulation of calcium ions in and out of the body

Calcium metabolism is the movement and regulation of calcium ions (Ca2+) in (via the gut) and out (via the gut and kidneys) of the body, and between body compartments: the blood plasma, the extracellular and intracellular fluids, and bone. Bone acts as a calcium storage center for deposits and withdrawals as needed by the blood via continual bone remodeling.

Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<span class="mw-page-title-main">Chlortalidone</span> Thiazide-like diuretic drug

Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

<span class="mw-page-title-main">Thiazide</span> Class of chemical compounds

Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.

<span class="mw-page-title-main">Gitelman syndrome</span> Medical condition

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

<span class="mw-page-title-main">Renal tubular acidosis</span> Medical condition

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by insufficient secretion of hydrogen ions into the latter portions of the nephron or by failure to reabsorb sufficient bicarbonate ions from the filtrate in the early portion of the nephron. Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents.

<span class="mw-page-title-main">Hypouricemia</span> Medical condition

Hypouricemia or hypouricaemia is a level of uric acid in blood serum that is below normal. In humans, the normal range of this blood component has a lower threshold set variously in the range of 2 mg/dL to 4 mg/dL, while the upper threshold is 530 μmol/L (6 mg/dL) for women and 619 μmol/L (7 mg/dL) for men. Hypouricemia usually is benign and sometimes is a sign of a medical condition.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

Hypercalciuria is the condition of elevated calcium in the urine. Chronic hypercalciuria may lead to impairment of renal function, nephrocalcinosis, and chronic kidney disease. Patients with hypercalciuria have kidneys that excrete higher levels of calcium than normal, for which there are many possible causes. Calcium may come from one of two paths: through the gut where higher than normal levels of calcium are absorbed by the body or mobilized from stores in the bones. After initial 24 hour urine calcium testing and additional lab testing, a bone density scan (DSX) may be performed to determine if the calcium is being obtained from the bones.

<span class="mw-page-title-main">Milk-alkali syndrome</span> Medical condition

Milk-alkali syndrome (MAS), also referred to as calcium-alkali syndrome, is the third most common cause of hypercalcemia. Milk-alkali syndrome is characterized by elevated blood calcium levels, metabolic alkalosis, and acute kidney injury.

<span class="mw-page-title-main">Bladder stone (animal)</span> Common occurrence in animals

Bladder stones or uroliths are a common occurrence in animals, especially in domestic animals such as dogs and cats. Occurrence in other species, including tortoises, has been reported as well. The stones form in the urinary bladder in varying size and numbers secondary to infection, dietary influences, and genetics. Stones can form in any part of the urinary tract in dogs and cats, but unlike in humans, stones of the kidney are less common and do not often cause significant disease, although they can contribute to pyelonephritis and chronic kidney disease. Types of stones include struvite, calcium oxalate, urate, cystine, calcium phosphate, and silicate. Struvite and calcium oxalate stones are by far the most common. Bladder stones are not the same as bladder crystals but if the crystals coalesce unchecked in the bladder they can become stones.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">Nephrocalcinosis</span> Medical condition caused by the deposition of calcium salts in the kidneys

Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe the deposition of poorly soluble calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined by progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. It may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium salts.

<span class="mw-page-title-main">Medullary sponge kidney</span> Congenital disorder of urinary system

Medullary sponge kidney is a congenital disorder of the kidneys characterized by cystic dilatation of the collecting tubules in one or both kidneys. Individuals with medullary sponge kidney are at increased risk for kidney stones and urinary tract infection (UTI). Patients with MSK typically pass twice as many stones per year as do other stone formers without MSK. While having a low morbidity rate, as many as 10% of patients with MSK have an increased risk of morbidity associated with frequent stones and UTIs. While many patients report increased chronic kidney pain, the source of the pain, when a UTI or blockage is not present, is unclear at this time. Renal colic is present in 55% of patients. Women with MSK experience more stones, UTIs, and complications than men. MSK was previously believed not to be hereditary but there is more evidence coming forth that may indicate otherwise.

Sodium cellulose phosphate is a drug used to treat hypercalcemia and hypercalciuria. It has been investigating for the prevention of kidney stones, but with limited efficacy.

<span class="mw-page-title-main">Distal renal tubular acidosis</span> Medical condition

Distal renal tubular acidosis (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the distal tubule and cortical collecting duct of the distal nephron. This failure of acid secretion may be due to a number of causes. It leads to relatively alkaline urine, due to the kidney's inability to acidify the urine to a pH of less than 5.3.

<span class="mw-page-title-main">Renal stone formation in space</span>

Renal stone formation and passage during space flight can potentially pose a severe risk to crew member health and safety and could affect mission outcome. Although renal stones are routinely and successfully treated on Earth, the occurrence of these during space flight can prove to be problematic.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

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  19. ↑ Kopf, Gregory S.; Lewis, Cindy A.; Vacquier, Victor D. (Sep 1983). "Methylxanthines stimulate calcium transport and inhibit cyclic nucleotide phosphodiesterases in abalone sperm". Developmental Biology. 99 (1): 115–120. doi:10.1016/0012-1606(83)90258-0. PMID   6194028.
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  21. ↑ McParland, B. E.; Goulding, A.; Campbell, A. J. (1989-09-30). "Dietary salt affects biochemical markers of resorption and formation of bone in elderly women". BMJ. 299 (6703): 834–835. doi:10.1136/bmj.299.6703.834-a. ISSN   0959-8138. PMC   1837680 . PMID   2510848.
  22. ↑ Hess, B; Ackermann, D; Essig, M; Takkinen, R; Jaeger, P (June 1995). "Renal mass and serum calcitriol in male idiopathic calcium renal stone formers: role of protein intake". The Journal of Clinical Endocrinology & Metabolism. 80 (6): 1916–1921. doi:10.1210/jcem.80.6.7775641. ISSN   0021-972X. PMID   7775641.
  23. 1 2 3 Coe, Fredric L.; Worcester, Elaine M.; Evan, Andrew P. (Sep 2016). "Idiopathic hypercalciuria and formation of calcium renal stones". Nature Reviews Nephrology. 12 (9): 519–533. doi:10.1038/nrneph.2016.101. ISSN   1759-5061. PMC   5837277 . PMID   27452364.
  24. ↑ Broadus, Arthur E.; Dominguez, Manual; Bartter, Frederic C. (Oct 1978). "Pathophysiological Studies in Idiopathic Hypercalciuria: Use of an Oral Calcium Tolerance Test to Characterize Distinctive Hypercalciuric Subgroups*". The Journal of Clinical Endocrinology & Metabolism. 47 (4): 751–760. doi: 10.1210/jcem-47-4-751 . ISSN   0021-972X. PMID   233682.
  25. ↑ Garcia, Clotilde D. (1991-10-01). "Natural History of Hematuria Associated With Hypercalciuria in Children". Archives of Pediatrics & Adolescent Medicine. 145 (10): 1204–1207. doi:10.1001/archpedi.1991.02160100136039. ISSN   1072-4710. PMID   1928018.
  26. ↑ Bruder Stapleton, prepared by F.; A Report of The Southwest Pediatric Nephrology Study Group (Feb 1990). "Idiopathic hypercalciuria: Association with isolated hematuria and risk for urolithiasis in children". Kidney International. 37 (2): 807–811. doi: 10.1038/ki.1990.49 . PMID   2407891.
  27. ↑ Worcester, Elaine M.; Coe, Fredric L. (Mar 2008). "New Insights Into the Pathogenesis of Idiopathic Hypercalciuria". Seminars in Nephrology. 28 (2): 120–132. doi:10.1016/j.semnephrol.2008.01.005. PMC   2362396 . PMID   18359393.
  28. ↑ Devuyst, Olivier; Thakker, Rajesh V (2010). "Dent's disease". Orphanet Journal of Rare Diseases. 5 (1): 28. doi: 10.1186/1750-1172-5-28 . ISSN   1750-1172. PMC   2964617 . PMID   20946626.
  29. ↑ Massey, Linda K; Roman-Smith, Helen; Sutton, Roger A.L (Aug 1993). "Effect of dietary oxalate and calcium on urinary oxalate and risk of formation of calcium oxalate kidney stones". Journal of the American Dietetic Association. 93 (8): 901–906. doi:10.1016/0002-8223(93)91530-4. PMID   8335871.
  30. 1 2 3 Sella, Stefania; Cattelan, Catia; Realdi, Giuseppe; Giannini, Sandro (2008). "Bone disease in primary hypercalciuria". Clinical Cases in Mineral and Bone Metabolism. 5 (2): 118–126. ISSN   1724-8914. PMC   2781204 . PMID   22460993.
  31. 1 2 Nacaroglu, Hikmet Tekin; Demircin, Gülay; Bülbül, Mehmet; Erdogan, Özlem; Akyüz, Sare Gülfem; Çaltik, Aysun (April 2013). "The Association between Urinary Tract Infection and Idiopathic Hypercalciuria in Children". Renal Failure. 35 (3): 327–332. doi:10.3109/0886022X.2013.764254. ISSN   0886-022X. PMID   23394064. S2CID   30279493.
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