After studying this text, readers ought to concentrate on the medical significance of urine calcium testing, together with its use and shortcomings in evaluation of parathyroid illness, stone formation, and FHH.
Chemistry examination 21001 questions and corresponding reply type are situated after this CE Replace article on web page 687.
Kevin F. Foley, Lorenzo Boccuzzi, Urine Calcium: Laboratory Measurement and Medical Utility, Laboratory Drugs, Quantity 41, Concern 11, November 2010, Pages 683–686, https://doi.org/10.1309/LM9SO94ZNBHEDNTM
Summary
As a result of calcium is required for muscle contraction and nerve signaling, the serum focus of calcium has apparent significance. Serum calcium additionally displays parathyroid hormone (PTH) operate and vitamin D standing. Though the medical significance of those 2 hormones and the ensuing focus of calcium within the serum is extensively recognized, the position of urine calcium testing will not be usually mentioned and is much less apparent.
The typical grownup retailer of calcium is roughly 1–2 kg. The overwhelming majority (99%) resides within the skeleton. Solely a fraction of the saved calcium is current in extracellular fluid and obtainable to be used within the type of ionized calcium. Ionized calcium is tightly regulated by PTH. Grownup calcium plasma concentrations are usually between 8.5–10.5 mg/dL (2.2–2.6 mmol/L). Most of this circulating calcium is sure to albumin. Due to this, adjustments in serum protein concentrations can have an effect on whole blood calcium concentrations. Calcium enters the extracellular fluid by means of absorption from the intestine and resorption from bone. It’s eliminated by means of secretion into the gastrointestinal tract and urine in addition to losses in sweat and deposition in bone.1
The advisable dietary allowance (RDA) for calcium varies with age and, for adults, with gender. Beneficial dietary allowance values for adults begin at 1000 mg per day. Urine calcium ranges will replicate dietary consumption. In a mean grownup urine pattern collected over 24 hours, 100–250 mg of calcium (15–20 mmol) is anticipated. For these on low-calcium diets 50–150 mg/day is anticipated, whereas these on a calcium-free weight loss plan can have 5–40 mg/day.2 It is usually necessary to notice that calcium excretion (CE) is closely influenced by sodium excretion. Low-sodium diets are likely to lower CE and vice versa.
Though a 24-hour assortment is finest, random urine calcium measurement might be carried out and is expressed in relation to creatinine. A traditional reference interval for the urine calcium (mg/dL):urine creatinine (mg/dL) ratio is <0.14. Values exceeding 0.20 are found in patients with hypercalciuria. In children, the calcium:creatinine ratio decreases steadily with time until approximately age 6. It is important to note this fact since most children will be falsely flagged as hypercalciuric using adult cut-offs. Elevated urine calcium (>300 mg/24 hr) is usually an indication of an overactive parathyroid gland. Parathyroid hormone is produced in response to serum calcium ranges. Parathyroid calcium-sensing receptors (CASRs) stimulate elevated PTH launch within the presence of decreased serum calcium ranges. Parathyroid hormone then works to extend serum calcium ranges. The will increase in serum calcium are achieved through elevated renal tubule reabsorption of calcium and simultaneous decreases in phosphorus reabsorption. The serum focus of phosphorus must be similar to that of calcium since each are held in equilibrium to one another; as 1 goes up, the opposite tends to go down. Parathyroid hormone additionally causes reabsorption of calcium from bone in addition to elevated synthesis of 1,25-dihydroxy vitamin D, which stimulates calcium absorption from the intestine. All of those actions result in elevated serum calcium. Hyperparathyroidism ends in extreme uptake and elevated concentrations of calcium in serum resulting in hypercalcemia and hypophosphatemia. That is then mirrored within the urine as hypercalciuria and hyperphosphaturia. Thus, urine calcium ranges are sometimes elevated within the setting of hyperparathyroidism. Nevertheless, one-third of hyperparathyroid sufferers have regular urine calcium, so this check will not be dependable in differentiating or diagnosing hyperparathyroidism.2
Calcium Crystals and Stones
Calcium is a typical ingredient in urine stones and crystals. Calcium oxalate (Ca[COO]2) crystals are probably the most incessantly noticed crystals in urine, and 75% of renal calculi have calcium oxalate as a element. Calcium oxalate crystals can type at any pH and have numerous microscopic morphologies. It’s estimated that about half of the oxalate in urine comes from ascorbic acid (vitamin C), which is a precursor to oxalate. Calcium oxalate crystals are additionally related to ethylene glycol ingestion, one other oxalate precursor. Calcium carbonate (CaCO3), the principle element of marine shells and egg shells, might be discovered as small granular crystals in alkaline urine. Calcium carbonate crystals are usually not frequent in urine however when current might be mistaken for micro organism. To assist discriminate these 2, acetic acid might be added to the pattern, inflicting the crystals to launch CO2 which seems as effervescence. Calcium phosphate (CaHPO4 or Ca[H2PO4]2) crystals can have totally different morphologies relying on their state of hydration and might be current within the urine sediment of impartial or barely alkaline or acidic urine. Though not all sufferers with calcium crystals current in urine will undergo from kidney stones, renal calculi might be attributable to calcium oxalate, CaCO3, or CaHPO4.
Acidification of urine helps forestall calcium from precipitating as salts and thus prevents falsely decreased measurements of urine calcium. Due to the attainable interference of crystals, acidification of urine to pH <2 or pH 4–5 is advisable by many producers of urine calcium reagents. Nevertheless, including acid to urine specimens presents some threat to technologists; it should dilute the specimen (though normally solely to a minor diploma), and it's time-consuming and sometimes requires coaching and monitoring at assortment websites. A latest research has questioned the necessity to acidify urine.3
Hypocalciuria
Hypocalciuria is usually mistakenly attributable to incomplete assortment (a random pattern regarded as an aliquot from a 24-hour specimen). Some medication can lower urine calcium, together with thiazide diuretics, benzothiadiazide diuretics (like chlorthalidone), and estrogen. Decreased urine calcium can be seen in hypoparathyroidism, pseudohypoparathyroidism (an absence of response to PTH slightly than decreased secretion of PTH), rickets, hypothyroidism, steatorrhea, and nephrosis. One other explanation for low urine calcium is familial hypocalciuric hypercalcemia (FHH), also referred to as familial benign hypercalcemia. This illness is usually initially misdiagnosed as hyperparathyroidism, however in contrast to hyperparathyroidism, FHH is not going to resolve with parathyroidectomy. Familial hypocalciuric hypercalcemia is now recognized to be attributable to numerous autosomal-dominant loss-of-function mutations within the gene coding for the CASR.4 The CASR responds to serum calcium and mediates suggestions inhibition of PTH launch. A loss-of-function mutation ends in a rising of the calcium threshold that triggers discount of PTH secretion. Serum focus of calcium is thus maintained at greater ranges since extra calcium is required to set off damaging suggestions. This ends in hypercalcemia, and since extra calcium is sequestered within the serum, hypocalciuria usually outcomes. You will need to word that hyperparathyroidism and FHH can present elevated serum PTH ranges. There are additionally recognized instances by which FHH sufferers have hypercalciuria.5
Hypercalciuria
Any illness inflicting will increase in serum calcium can result in will increase in urine calcium. Along with hyperparathyroidism, different ailments embrace a number of myeloma (or any osteolytic neoplasm), osteoporosis, vitamin D overdose, renal tubular acidosis, hyperthyroidism, Paget’s illness, and sarcoidosis. Medicine containing calcium (reminiscent of some antacids) and calcium dietary supplements can result in direct will increase in urine calcium. The diuretic spironolactone can even trigger will increase in urine calcium since it’s given as a calcium salt and seems to lower tubule reabsorption of calcium. Androgens reminiscent of nandrolone and therapy with progress hormone can even trigger will increase in urine calcium. Acetazolamide and systemic corticosteroids are additionally related to elevated CE.
Sufferers who’ve alterations in serum calcium ranges are sometimes asymptomatic on the time their irregular calcium ranges are found by the medical laboratory. Nevertheless, sufferers with irregular calcium ranges can current with extreme indicators and signs, reminiscent of tetany and seizure. Different medical signs suggestive of alteration in calcium metabolism might embrace perioral and peripheral paresthesias, carpal and pedal spasms, muscle aches, melancholy, nervousness, fatigue, constipation, stomach ache, polyuria, and polydypsia. Irritability and lethargy often is the solely presenting signs in an toddler. Maternal hypercalcemia may end up in an elevated threat of spontaneous abortions, fetal demise, and neonatal hypocalcemia. Maternal hypocalcemia could cause neonatal hyperparathyroidism with irregular serum calcium ranges and osteitis fibrosa cystica.6 Unrecognized hypoparathyroidism and FHH in girls who have been identified after the beginning of their infants have been reported as properly.6
Though not ordered on a frequent foundation by major care clinicians, urinary calcium dedication might have a big affect on the prognosis and therapy of some ailments. Within the preliminary investigation of figuring out the reason for irregular calcium metabolism, a 24-hour urine assortment for calcium, urine quantity, and creatinine must be carried out together with blood testing. The two strategies mostly utilized by clinicians to find out abnormality in renal excretion of calcium are measurement of 24-hour urine CE or calculation of the 24-hour urine calcium/creatinine excretion ratio (CR).7 Latest analysis, nevertheless, appears to point that these checks might not adequately establish hyperparathyroid sufferers. As an alternative, the calculation of the calcium/creatinine clearance ratio (CCCR), also referred to as the fractional excretion of calcium (FEca), could also be a greater methodology by which to establish the reason for irregular calcium metabolism.7 The CCCR might be calculated from simultaneous determinations of plasma calcium and creatinine together with the 24-hour renal excretions of calcium and creatinine and making use of the next system: (24-hour U-calcium/P-total calcium) / (24-hour U-creatinine/P-creatinine).8,9
A fasting urine calcium may be helpful in uncovering calcium overdose (elevated absorption from the intestine). If a 2-hour urine assortment is obtained after a 14-hour quick, the urine calcium:creatinine ratio ought to fall to <0.15. If it is >0.15, metabolic/nephrogenic hypercalciuria is suspected.10
Use in FHH and Major Hyperparathyroidism – “calcium 24 hour urine”
The prognosis and coverings differ considerably between FHH and first hyperparathyroidism (PH). Familial hypocalciuric hypercalcemia is often a benign illness requiring no therapy, whereas surgical intervention is required to deal with PH so as to forestall long-term problems of hypercalcemia.7 Can urine calcium measurement assist differentiate PH from FHH? Tips have been instructed stating {that a} CCCR of <0.010 implicates FHH, whereas a CCCR of >0.020 is extremely suspicious of PH.9,11 Christensen and colleagues in contrast CCCR measurement with CE and CR in 54 sufferers with FHH (all with mutations within the CASR gene), and 97 hypercalcemic sufferers with histological affirmation of PH.7 They discovered the CCCR measurement was marginally higher than CE or CR at differentiating the two ailments. At a cut-off level of <0.020, the CCCR index of their inhabitants included 98% of all sufferers with FHH however nonetheless included 35% of sufferers with PH. Though this cut-off nonetheless included some PH sufferers, the CCCR misclassified fewer PH sufferers than CR or CE. The authors concluded CCCR may be helpful as an preliminary screening check for FHH, adopted by CASR gene evaluation for sufferers <0.020 to rule in/out FHH. Urinary calcium measurements may play a task in figuring out sure sufferers with osteoporosis who type kidney stones. Sufferers in danger for stone formation usually observe totally different therapy choices for his or her osteoporosis. Giannini and colleagues decided that measuring urinary CE in osteoporotic sufferers might assist establish these sufferers with idiopathic hypercalciuria and calcium nephrolithiasis.12 As identified of their research, there are information to assist the affiliation between low bone density in nephrolithiasic sufferers with hypercalciuria however not in these with out hypercalciuria. Extra importantly, the creator factors out a lot of retrospective and potential research displaying thiazides (which lower urine calcium), have been related to a discount in fracture incidence,13–16 and a rise in bone density.17–21 Giannini and colleagues recommend the vast majority of the sufferers of their research might undergo from a diet-independent type of hypercalciuria just like that seen in sufferers with kidney stones and low bone density.12 They conclude that urinary CE must be measured in osteoporotic sufferers so as to establish this group of sufferers.
Use in Assessing Stones
On the whole, sufferers with calcium urolithiasis excrete extra lithogenic substances (calcium and oxalate) in urine than non-stone formers. Additionally they usually secrete much less of the stone-inhibitory substances citrate and magnesium. But measurement of urine calcium will not be thought of a superb predictive measurement for stone formation. Calcium-based threat markers for urolithiasis have been studied and embrace ratios such because the calcium/magnesium ratio, the calcium/citrate ratio, and the (calcium * oxalate)/(magnesium * citrate) ratio.22 Since stone formation is multi-factorial and inherently variable, at the moment neither calcium nor some other marker for urolithiasis threat is properly accepted.
Though urine calcium will not be a decisive marker for stone formation, urine calcium measurement might play a task in figuring out sure sufferers who type kidney stones because of the presence of systemic illness (significantly PH). Parks and colleagues in contrast laboratory options and outcomes of therapy in urinary stone-forming sufferers with hyperparathyroidism to these with out systemic illness.23 The authors concluded that the hypercalciuria in PH sufferers who fashioned stones was higher than the hypercalciuria of the stone-formers with out systemic illness. Thus, measurement of the CCCR would possibly assist discriminate stone-formers with PH from these with different issues. This data can be helpful in figuring out acceptable therapy intervention. Apparently, surgical therapy of the PH didn’t fully resolve the hypercalciuria or hypophosphatemia in these sufferers, suggesting the presence of one other underlying dysfunction. This demonstrates the advanced nature of calcium homeostasis in that PTH is just one of the gamers concerned.
Use in Kids
Figuring out urine CE in kids is usually a problem since reference values for the urine/creatinine ratio are usually not properly outlined and differ in response to weight loss plan. Timed 24-hour urine collections might be obtained in older kids, however in youthful kids a random spot urine calcium creatinine ratio repeated on 2–3 events on the identical time of day is incessantly required to evaluate urine CE.24 The calcium:creatinine ratio on the second voided urine pattern of the day after an in a single day quick most intently pertains to a 24-hour urine calcium degree.
Childhood rickets is an instance by which urinary calcium measurements are helpful. Within the prognosis of rickets, establishing an inappropriately excessive urinary CE within the face of low serum calcium ranges is necessary.24 Measuring a urine CR ratio can be a part of the preliminary analysis in kids who’ve urinary tract calculi as it may possibly assist establish metabolic illness whether it is current. Hypercalciuria is the most typical metabolic explanation for stones in Western kids and no particular trigger is ever decided in 1 / 4 of the instances.25