She crystallized, perhaps into calcium carbonate, hence my putting her here at the beginning of our sojourn into the vast territories of calcium metabolism and the hypercalciuric states. If I were to single out one condition that dominates stone disease prevention because of sheer commonness and reliable means of treatment it would be this one.
I have put off the crucial topic of hypercalciuria for the first year of this site because I wanted to build a proper foundation.
It is time to tackle the problem of high urine calcium itself, what happens when it is high, why it might be high, what levels pose stone risk, and how it is best treated so far as we know.
This article lays out the relationships between urine calcium and stone risk, names the important causes of high urine calcium in stone forming people, and the other problems high urine calcium may be related to.
It is an introduction: Long, but brief in comparison to what is a major component of stone disease and its clinical management.
What is Hypercalciuria?
To me the most immediate definition is about stones: At what level of urine calcium is the risk of new stone onset increased?
The best information to date arises from long term longitudinal data contributed by two cohorts of nurses and one of physicians exploited by Dr. Gary Curhan. In each cohort, some people became stone formers, and most did not. Gary obtained 24 hour urines in a cross section from all three cohorts, and was able to relate the level of urine calcium excretion to the risk of forming stones.
Along the horizontal axis urine calcium excretions are groups into 6 bins; above each bin the relative risk of becoming a stone former is presented for the two nurse cohorts (all women, and in red bars) and the physician cohort (all men and in blue bars). The dashed line is at 1, meaning the baseline of risk for the population which was at taken at <100 mg/day of urine calcium loss.
The relative risks are given in the manuscript as an average (mean) value and an upper and lower 95% confidence limit. But I am showing only the lower 95% confidence limit (solid bars) and means (lighter bars).
For example, in the 100-149 bin the mean relative risk for the first of the two female (red) cohorts is 1.26 (plotted up from 1 as a light bar), the lower limit is 0.84 (plotted down from 1 in a solid red bar) and the upper limit is 1.91 (not plotted).
I am after a measure of risk that is robust: In which bin is it very likely that risk is increased above the 100 mg/day baseline?
For me, that is when the lower limit for the relative risk is above 1.
For example, the value of the lower 95% risk confidence limit of the 100-149 bin, in the first of the two nurse cohorts – 0.84 – does not connote a high likelihood of significant risk compared to 100 mg/day of urine calcium.
On the other hand, risk is very likely present above 200 mg/day of urine calcium, because the lower 95% limit is above 1 in all three cohorts. Of interest, women and men do not seem to differ, so this one criterion applies to both sexes equally.
Also of interest and great importance, there is a dose response.
Higher and higher urine calcium levels are associated with higher and higher relative risk. This is good supportive evidence of a causal connection and best seen by the position of the means which are at the tops of the bars..
The direction of causality is not determinable from observation, but I vote for higher urine calcium causing stones not that being a stone former somehow raised urine calcium.
My vote is because of the other science.
This site has belabored the point that supersaturation drives crystallization, and stones are made of crystals. In preparation for this new series of articles on urine calcium I have gathered the main articles on the stones themselves and on supersaturation into a pair of ‘walking tours’ which present them in context and with with commentary. These are the foundational articles upon which the effects of urine calcium and other urine constituents can be assembled to produce a reliable picture of how stones form and how they can be prevented.
Here, I simply note that higher urine calcium loss will increase average urine calcium concentration for any given urine flow rate, and higher calcium concentrations will in general produce higher SS values for calcium phosphate and calcium oxalate and therefore higher risk of stones. So hypercalciuria, to me, and for good reasons, is almost certainly a cause of calcium stones via increase of SS which is the prime measure of the energy that drives crystallization.
Upper End of the Normal Range
A valid and alternative definition of hypercalciuria is that it consists in very high urine calcium excretion, and a way to gauge the meaning of ‘very high’ would be values at the upper end of the normal range. This idea of the ‘upper end’ is usually taken as above the upper 95% of values encountered in surveys of people without known diseases.
The Curhan data actually give a reasonable measure of this ‘upper end’ from the means and 95% limits of the non stone formers in the three cohorts. The lower dot marks the position of the lower 95th percentile of urine calcium for the two nurse cohorts and the physician cohort. The upper dot gives the upper 95th percentile (two standard deviations above the mean for those technically inclined). The intervening bars are for visual effect.
For those who want to study hypercalciuria, as an example, and want a reliable gauge of who is ‘really high’ the three figures are 374 372 and 351 mg/day for the three groups.
Using smaller and less well selected populations, many investigators have derived somewhat different upper limits for defining hypercalciuria. For example urine calcium excretions above 250 mg/day or above 4 mg/kg body weight are common as in this typical kind of research publication. In our own reviews we have frequently used 250 mg/day for women, 300 mg/day in men, and 4 mg/kg body weight either sex as upper limits to define hypercalciuria.
I think that the Curhan values are ideal for clinical practice. People with calcium stones and urine calcium levels above 200 mg/day have increased risk from their urine calcium and one aspect of their treatment can be to reduce urine calcium.
That is to say, physicians look at all possible factors that may be increasing risk in a patient, sort them out and select for treatment those most promising and practical to treat. Among them will often be urine calcium and Curhan has given us good targets and criteria.
For research, I am more flexible. Strictly speaking the 95% upper limits are a kind of ideal, but if you want to understand mechanisms that raise urine calcium one might be better served by selecting cohorts with a range from high normal to very high. These are research design decisions, and all I mean to say here is we have decent ideas about normal ranges and stone risk, and it is possible from them to derive appropriate approaches to clinical research on hypercalciuria.
Diseases That Cause Hypercalciuria in Stone Formers
Let me be clear about goals here. Each of these diseases will get its own articles, or perhaps many articles, so this is not meant to be a proper exposition but merely an introduction.
For this reason referencing is light and I mainly make assertions which are commonplace and can be found in any textbook or review article. When I get to the diseases one by one I hope to offer considerably more than is commonplace.
Primary hyperparathyroidism (PHPT)
About 3 – 5% of calcium stone formers have this curable disease, on average, so its detection is crucial for proper patient care. As a reference I have used my own publication because it contrasts patients with this disease to ordinary stone formers, is available as a free pdf, and, perhaps, because I wrote it.
One or more of the parathyroid glands enlarges and produces an excess of parathyroid hormone (PTH). PTH signals kidney cells to retain calcium by reabsorbing a higher fraction of calcium that is filtered by the glomeruli. It stimulates production of the active form of vitamin D (calcitriol) and that in turn increases the efficiency of GI absorption of calcium from foods. Finally PTH increases bone turnover so more calcium than normal leaves the bone and can be lost in the urine.
The increased bone calcium loss and increased GI calcium absorption are balanced by increased urine calcium losses, and these can be very impressive. The high urine calcium losses raise urine supersaturation with respect to calcium oxalate and calcium phosphate so stone risk rises and patients with this disease not uncommonly present themselves as stone formers.
High rates of mineral loss from bone cause bone mineral depletion, and bone disease is well known to occur. If the disease is cured in a timely way bone healing is expected.
The action of PTH to increase the fraction of filtered calcium that is reabsorbed causes blood calcium to rise. The increase is often modest.
Being rarely malignant, the enlarged parathyroid glands can be removed surgically with expectation of a cure, so this disease is a curable cause of kidney stones and bone disease.
The diagnosis depends upon finding high urine calcium excretion, a serum calcium concentration above normal for the laboratory making the measurement, and a serum PTH value which is not suppressed below the normal range.
However, there are a few cautions that must be considered always. Even if everything I have just said is true, there are artifacts that lead to mistakes in diagnosis and could lead to unnecessary surgery. All thiazide type diuretics can raise serum calcium, so testing needs to be done after 2 weeks off the drug. Lithium can raise both serum calcium, serum PTH and even urine calcium, so is a real fooler. Hyperthyroidism, including that induced by too much thyroid hormone replacement, can raise serum and urine calcium although it does suppress serum PTH. The serum for PTH must be the one for the calcium – same blood draw for both, and must be drawn fasting overnight.
The relationship between PTH and serum calcium is often misunderstood. The calcium balance systems are elaborate and tend to be self regulating, so increased PTH secretion leads to increases in serum calcium and calcitriol both of which, through negative feedback on the glands, bring PTH down toward or even to normal, but never below normal. Therefore PHPT is diagnosed when the serum calcium is above normal and the PTH is not below normal.
Here are the serum and urine calcium values from the PHPT cases in our publication – all proven surgically – shown in large dots, normal people (medium dots) and thousands of points from stone formers without any systemic disease – fine spray of tiny dots (common stone formers). The vertical dashed lines are the normal range for blood calcium in our kidney stone laboratory, the horizontal line is just below the level where stone risk from urine calcium begins (200 mg/day).
The patients all had serum calcium values above normal but many were just slightly high. Urine calcium was a lot higher than in ordinary stone formers, but even in those the plume of fine dots rose far above 200 mg/day. Note that some normal people had values above 200 mg/day.
After surgical cure (right panel) the PHPT cases, normals, and treated common stone formers who had no systemic disease all contracted into a small region, but not a few urine calcium values were above the fateful 200 mg/day limit still.
The curves outside the boxes show the distributions; see how the hyperparathyroidism points (dashed lines) spread out far above those for normals and ordinary stone formers, then fall back with surgical cure.
Properly speaking this would be high urine calcium excretion, normal blood calcium, and reasons to think that an abnormality of parathyroid gland function was responsible for the high urine calcium – which is the only abnormality. One such reason could be an elevated level of serum PTH, and such levels are encountered from time to time. Another could be blurring of the true upper limit for serum calcium; not all laboratories are equally crisp. A third could be, and this is speculative, that along the course of PHPT glands might lose their normal CaSR responsiveness, so that PTH levels are no longer down regulated normally by serum calcium. In another article I will explore this problem. Right now, I believe it is wiser to wait for hypercalcemia before committing to neck surgery in hopes of cure and treat the hypercalciuria as if it were idiopathic hypercalciuria – see below. PHPT will ultimately declare itself in most cases. The reference in the link above is supportive of my suggestions because the authors expect elevated serum calcium in PHPT, as I do.
Being so caught up in the maintenance of a normal serum calcium, the parathyroid glands will react to any threat with increased or decreased PTH secretion as required to restore that normal value. Low calcium diet, vitamin D deficiency, GI diseases with calcium malabsorption for any reason, chronic kidney disease with its odd form of calcium aberrations, all these will and do cause increase of PTH secretion and raised serum PTH levels. None of these are hypercalcemic states, and most have a low urine calcium loss. Stones may be present but for reasons other than parathyroid abnormalities, and often other than level of urine calcium. For example, acid urine pH from kidney disease can cause uric acid stones; high urine oxalate from bowel disease can cause calcium oxalate stones. All I mean to say here is that isolated increase of serum PTH with low or even normal urine calcium and normal or low serum calcium levels are usually not an occasion for parathyroidectomy, but call for a diagnosis of their own. As I have by said to excess, this is an issue that deserves more than an introduction. The link for normocalcemic primary hyperparathyroidism is useful for this topic and the one below.
Familial Hypocalciuric Hypercalcemia (FHH)
High serum calcium with low urine calcium excretion – below 100 mg/day is common – is almost never primary hyperparathyroidism but rather a mutation of the PT gland CaSR that raises its sensitivity so serum calcium can be low, serum PTH normal, and urine calcium quite low. When FHH patients have stones the stones are not due to high urine calcium but some other cause, and most importantly parathyroid surgery is a mistake.
In my long experience I have seen far less than 1% of calcium stone formers present with this condition. A reputable source of information about Sarcoidosis fails to mention kidney stones so far as I could see.
Briefly, sarcoidosis is a disorder of the immune system and the cells which proliferate and enlarge lymph nodes, liver, spleen and other tissues produce calcitriol. So the physiology is that of unbalanced high calcitriol production.
As I have mentioned above, calcitriol increases GI calcium absorption, so food calcium entry into the blood increases. I have not mentioned but say now that calcitriol increases net bone mineral losses mainly by reducing bone production. Calcitriol is a steroid hormone and like many steroids acts on the nuclei of cells. It acts on parathyroid cells to shut down production of PTH so tubule reabsorption of filtered calcium is reduced as compared to primary hyperparathyroidism.
The increases in bone mineral loss and GI calcium absorption raise urine calcium excretion as in hyperparathyroidism. Because PTH is suppressed below normal, serum calcium may not rise or when it does so rises only slightly at first.
This means that in many instances suppressed serum PTH may be the only laboratory clue to sarcoidosis as a cause of hypercalciuria and stones. Clinically sarcoidosis is often diagnosed from its signs and symptoms, as noted in the reference from the National Heart and Lung institute. I have had cases which I diagnosed de novo being without obvious signs otherwise because of suppressed PTH with very high urine calcium and even elevated serum calcium.
Serum calcium rises when the flows of calcium from bone and GI absorption are very marked or when the efficiency of renal calcium removal falls.
This latter can occur because of calcium itself. It can reduce water and salt conservation and therefore reduce the blood volume and therefore filtration. Any reduction will tend to increase serum calcium, and increases in serum calcium will reduce filtration and water losses, so a kind of unhappy cycle begins. How calcium acts to reduce calcium reabsorption and that it also acts on filtration itself comes later, not in this article but in those perhaps months from now.
Vitamin D3 is made in the skin or consumed in pills, and in the liver converted into 25 hydroxy (OH) vitamin D (25(OH)D3). The enzymes responsible for the conversion are called CYP2R1 and CYP27A1.
25(OH)D3 circulates and is itself biologically active, but has a larger fate. Some is converted by kidney cells into 1,25(OH)2D3 (calcitriol for ease of writing and reading) and it is this molecule which more powerfully activates tissue responses in the GI tract, kidneys, bone, and – as already mentioned – parathyroid cells. The enzyme which activates 25(OH)D3 to calcitriol is called CYP27B1.
CYP24A1 is a general purpose inactivator of 25(OH)D3 and calcitriol. It converts the former into inactive molecules in liver. In kidney it converts calcitriol into other inactive molecules. If this degrading enzyme is deficient because of mutations, calcitriol levels increase as in Sarcoidosis, and one gets a similar picture of high urine calcium suppressed serum PTH and high normal to high serum calcium, with kidney stone formation as a consequence of the high urine calcium.
This is a rare condition; in my lifetime of practice I have encountered only 2 cases I know of.
Vitamin D and Calcium Supplement Excess
Certainly, these OTC materials are associated with increases of urine and even serum calcium, especially noted in menopause when their use is prevalent. Causality is not certain. For example, serum 25(OH)2D3 levels between 20 (a low number) and 100 (a high number) were not associated with kidney stones in a small sample of 2012 people. However in a large trial, it appeared that calcium supplements, not food calcium, might be specifically a risk for stones. Calcium supplements might be a particular hazard in people prone to high urine calcium excretion by their genetics.
Distal Renal Tubular Acidosis
I have referenced our paper not out of community pride but because it is the only one which describes the papilla and separates stones from nephrocalcinosis. In a massive surgical practice at the Kidney Stone Center at Indiana University we could find only 5 cases on whom we have operated and obtained research information about the papillary tissues.
All five had the expected reduction of serum bicarbonate with increased serum chloride (no elevated anion gap), alkaline urine pH, and reduced serum potassium – from the obligatory bicarbonate driven kaluresis. Several were hypercalciuric.
You can tell this from the x rays in the upper two panels. Before percutaneous nephrolithotomy nephrocalcinosis was dramatic; afterwards, few calcifications were present.
In the middle left panel you can see stones in the calyces during surgery, and in the right middle panel you can see the papilla after the stones were taken out. It has some calcifications in the tissue which are plugs in tubules. These plugs are shown by a micro – CT of a tiny biopsy from the papilla (lower left) and in a histological section (lower right)
Stone cultures were positive, perhaps because these patients had many prior procedures for multiple stones.
Deposits of calcium phosphate crystals affected virtually all of the Bellini ducts and though each deposit was small plugging on average replaced much of the papillary tissue. Despite this, kidney function as measured clinically was not remarkably abnormal, and the cortex of the kidneys not remarkably damaged.
In 1980 I presented our only 6 patients with stones and distal RTA out of over 1,000 stone formers to date, of whom 4 were from one family. They all had low bicarbonate and high chloride in their serum, as expected, an alkaline urine pH, and were unable to lower the urine pH with an acid load. Only one was convincingly hypercalciuric.
The essence of dRTA in stone formation is this: By inheritance or because of Sjogren’s syndrome, SLE or other immune mediated diseases the ability of the collecting ducts to lower urine pH normally is diffusely impaired, not in the patchy way one might expect from tubule plugging with crystals but throughout the medulla and papillae. High tubule fluid pH and, when present, hypercalciuria raise supersaturation with respect to calcium phosphate and diffuse plugging occurs with considerable damage and loss of tissue.
Perhaps because of its diffuse nature, dRTA does appear to lead to overall reduction of renal function if enough cases can be found and comparisons made to other forms of stone disease. In this study we had 1,856 patients with stone analyses and renal function, as well as diagnoses, all from our Kidney Stone Prevention Program at University of Chicago – the program that brings you this website.
Measured creatinine clearances are shown as means with standard errors for all stone types on the left, and by diagnostic category on the right. Note that RTA, cystinuria, obesity bypass patients, and a miscellany of other rare disorders (like sarcoidosis and CYP 24A1 defects) shared a distinct reduction of renal function, whereas the common calcium stone types without systemic diseases, and even primary hyperparathyroidism (HPT), had no reduction compared to normal (N). ID refers to idiopathic hypercalciuria, people who have high urine calcium losses without obvious disease.
What does all this mean?
Distal RTA is very uncommon, colorful, easily diagnosed by blood abnormalities, family history of like diseases, and the presence of immune diseases. The label RTA may be misapplied to patients with many calcium phosphate stones because they produce an alkaline urine pH; that is not true RTA, but how phosphate stone formers are.
More Rare Genetic Mutations
These conditions are almost always evident in childhood, very rare, and not what a clinician in the practice of stone prevention expects to encounter. However every once in a while they do show up. The best reading source for all of the genetic hypercalciurias is OMIM, the wonderful online library that is free to everyone. In reading the tiny blurbs below keep in mind that almost no stone formers have these rare diseases, that those who have them present typically as ill children, even infants.
Bartter Syndromes 1-3
These are gene defects of transporters in the thick ascending limbs of the loops of Henle (In case you forgot or never knew the nephron segments this article has a nice picture). There is hypercalciuria but also a picture that resembles lasix use because lasix acts on this segment. Urine losses are high for sodium, potassium, and chloride, and people with these diseases are prone to low blood pressure if they do not get enough sodium replacement. The blood bicarbonate is high, potassium is low.
Bartter Syndrome 5.
There is excessive signalling of the cell surface calcium receptor (CaSR) which produces a lasix like picture but because of the specific problem serum calcium is low and so is serum magnesium. The parathyroid glands are regulated by serum calcium via via the CaSR which is the reason for the low serum calcium level.
Autosomal dominant hypercalciuric hypocalcemia
The CaSR is altered genetically but the specific alteration causes a more marked change in serum calcium than in thick ascending limb function, so the serum potassium and bicarbonate can be normal. These two diseases BS 5 and ADHH are essentially on a spectrum and resemble each other.
A genetic mutation in a chloride transporter leads to hypercalciuria and, in males especially, progressive kidney disease. The serum values are normal apart from reduced kidney function.
Given the nephrocalcinosis and many stones, one might think MSK is a cause of extreme hypercalciuria, but that is not the case. Among our 12 cases that were proven to be MSK during surgery and with papillary biopsy, the average urine calcium was 250 mg/day, just above the Curhan threshold for significant risk. SS values for calcium oxalate averaged 7 and for CaP 1.3, values scarcely above those encountered within normal populations or among common uncomplicated calcium stone formers.
We noticed the same in our much earlier paper on MSK diagnosed in the era of intravenous pyelography. We have already mentioned that among our two MSK series serum levels showed none of the abnormalities of renal tubular acidosis (low bicarbonate and potassium) and urine pH was not high (6.1 in our recent series). Ductal and clinical stones were on average calcium oxalate, not calcium phosphate. We believe the stones form in the stagnant recesses of the collecting duct cysts, abetted by a very modest bias of urine calcium excretion above the normal median value. This is what one expects when supersaturated urine is trapped in place, and supersaturation inevitably expresses itself in gradual crystallization.
What is It?
In those two words you can find the major preoccupation of my life as a clinical investigator. To the mechanisms responsible for this common abnormality I have devoted my energies since I first began, in 1969.
The reference in the link above is to a review by my colleague Dr. Elaine Worcester whose brilliant research has clarified how the kidney goes about raising the urine calcium in this condition.
IH is not a disease.
It is a stone risk.
And that risk can be ascertained in any given person from the Curhan data in the first figure in this article.
People with high urine calcium excretions who do not have any of the diseases I have mentioned, or any of the others I have not – for pity and reasonable length of this article – mentioned thus far, have hypercalciuria that is ‘idiopathic’, of or from themselves or itself if you wish. They are the top of the mark among normals.
No red or green line separates IH from normal. Just as high blood pressure is a risk factor for stroke and heart disease, hypercalciuria is risk factor for disease – stones and bone disease, which is why I have devoted to its study so much of my life.
Being one end of the human distribution, IH may be found in your next door neighbor, or even your spouse and you would not know unless they are tested. And they will not be tested unless they get stones, or bone disease, or their family members get these diseases. If testing is done nothing will be found but high urine calcium, enigmatic, distinctive yet bland, but bespeaking a complex physiology.
Where Does the Extra Calcium Come From?
In the named diseases, hypercalciuria comes from bone and food calcium, and the same is true for IH. It has to be so, there are no other sources. But IH is not a disease, so we are seeing in IH a magnification of the usual losses of bone and diet calcium in urine, meaning that one or both of these must be increased. Certainly, as I will show in other articles, diet calcium is absorbed more efficiently in IH than in normal people. But bone mineral can be lost in excess, and bone disease can result.
It is for this reason, Dr. David Bushinsky, a distinguished bone and mineral investigator and internationally recognized authority in calcium metabolism, has proposed that every stone clinic is a bone clinic. Stone formers have the potential to develop bone disease if not properly cared for. Though their stones are an immediate reason for attention and a prime focus of care, bone health is also an inescapable concern.
How Can The Urine Calcium Be Lowered?
Toward the lowering of urine calcium and consequent prevention of stones – and preservation of bone mineral – we have some useful trials using thiazide diuretic type drugs. Likewise, some trial evidence favors reduction of diet sodium intake, to which I have alluded without presenting evidence.
Why Are We Ending Here?
It could seem ungracious to end here, without more details about IH or the many named hypercalciuric diseases, but this article is already very long, and what remains is a massive amount of information. I plan for many articles on hypercalciuria, the named diseases that cause it, and especially on IH itself because of its central role in stone disease and because it is a personal interest of mine and of those I work with.
Here I mean merely introductions, as at a cocktail party.
It seems probable to me that in doing right by this topic the articles on this site could double in number, although that may be an overestimate.
Check by from time to time, and you will find more.
Regards, Fred Coe