Idiopathic hypercalcinuria (IH) is a condition including an excessive urinary calcium level with a normal blood calcium level resulting from no underlying cause. IH has become the most common cause of hypercalciuria and is the most serious metabolic risk factor for developing nephrolithiasis. IH can predispose individuals to osteopenia or osteoporosis, 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. 50%-60% of nephrolithiasis patients suffer from IH and have 5%-15% lower bone density than those who do not.
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, 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. Other suggested IH be considered a daily urinary excretion of >4 mg of calcium per kg of body weight, 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. The only discernable feature between the two is the normal blood calcium level associated with IH.
Signs and symptoms IH can be presented with many urinary associated signs and symptoms mostly seen in children. They include:
Urinary incontinence, pollakiuria, and nocturnal enuresis Kidney stones and lithiasis Urinary tract infection (UTI) Hematuria, sterile leukocyturia and discrete proteinuria Dysuria and chronic abdominal pain
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. Others estimate IH may arise due to excessive expression of vitamin D receptors. (VDR) or a deficiency in enzymes within the renal tubules.
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. 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. 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. The increased expression of VDR in the intestinal walls may result in this.
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. 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, 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.
Increased rate of bone resorption It was found that IH patients had lower bone density, suggesting increased bone resorption. Bone resorption involves the breaking down of bone tissue and the transfer of calcium ions into the blood. Bone resorption is carried out by specialized bone cells known as osteoclasts. 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, 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. The high level of calcitriol found in hypercalciuria patients mentioned earlier stimulates higher rates of bone resorption and lowers bone formation. 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.
Genetic IH has been considered a disorder affected by both environmental and genetic factors and has a heterogeneous pathogenesis. 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. IH is believed to have an autosomal dominant transmission pattern, as it was not correlated with gender and was observed in all generations. Pak et al. and Nicolaidou et al. identified the same pattern. Additionally, different hypercalciuria forms within a family were discovered in Lerolle et al., confirming an autosomal dominant transmission.
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