IDIOPATHIC HYPERCALCIURIA (IH)

IMG_2303

VIDEO: About 27 minutes with a break at 15 minutes

Perhaps the most common abnormality among calcium stone formers, idiopathic hypercalciuria (IH) causes calcium kidney stones and can lead to bone mineral loss and fracturing bone disease. Proper treatment requires a high calcium intake, a low sodium intake, moderation of very high protein intakes, avoidance of refined sugar loads, and – not rarely – use of diuretic drugs which can lower urine calcium losses, prevent stones, and protect bones.

Why The Bathers?

Bone seems, to me, a bather in a bathtub. Calcium flows in from faucets – the GI tract – and out down the drain – the kidneys – as they regulate serum calcium – the height of the water in the tub. I realize the bather does not take up or lose water, but if you ponder the image awhile you may see in it what I see.

The Large Bathers (1884-87) of Renoir and The Large Bathers (1900-1906) of Paul Cézanne both reside in the Philadelphia Museum of Art, and I, though I love them both, could choose just one.

Toward the end of summer, surrounded by gardens, I chose the beguiling Renoir. In winter, the gray stones of my university might have swayed me toward Cézanne’s distant, dark, and brooding goddesses.

What is Idiopathic Hypercalciuria?

What is Hypercalciuria?

As hypertension is defined by blood pressures that associate with stroke, heart failure, and heart attack, hypercalciuria is defined by urine calcium excretions that associate with stones.

PQ RISK VS URINE CALCIUM LOW AND MEAN OVERPLOTTED.jpg

Increasing urine calcium losses associate with increasing risk of stones in two cohorts of women – red – and one of men – blue. Urine calcium is along the horizontal axis in six bins. The average relative risk of forming stones is marked by the tops of the bars. A value of 1 means no higher than among people with urine calcium below 100 mg/day – the reference population.

The lower 95th percentile of risk is at the bottoms of the bars. When the bottom of a solid bar lies above one, which is the case for all bars from 200-249 mg/d on, increased risk is very likely present. So the threshold of hypercalciuria is 200 mg/d both sexes.

Diet was not controlled, so we do not need special diets to diagnose hypercalciuria using this criterion.

As the urine calcium rises, risk – top of the bar – rises in smooth progression.

What Does ‘Idiopathic’ Mean?

The overwhelming majority of hypercalciuric stone formers have none of the many diseases that can raise urine calcium excretion. Their urine calcium exceeds 200 mg/d for no obvious reason – idiopathic, arising of itself, without overt cause.

Normal Calcium Excretion

normal uca male anf female.png

Since 1900 scientists have collected 24 hour urine samples from people in clinical research units, perfect collections, and measured urine calcium. I collected all such values I could from published papers – a tiring exercise. Here is my yield of values from normal adult men (blue) and women (red).

The threshold of clinical hypercalciuria, 200 mg/day, resides at about the 75th percentile: 25% of normal people are above it. But stone formers are perhaps 7-10% or less of the human population. So hypercalciuria raises stone risk, but not everyone gets the stones.

Likewise, stone disease is familial, but IH alone does not fully explain why. Presumably other inherited factors matter.

Decades ago we used the 95th percentiles of these two distributions, at about 275 and 325 mg/d of calcium for women and men, to define ‘hypercalciuria‘. No doubt such high values confer risk of stone, but they are too high for clinical use. They remain useful in research to define people with extremely high urine calcium values.

Hypercalciuria Raises Supersaturation and May Promote Plaque

Supersaturation produces and enlarges crystals and therefore stones. We now have superb evidence that rising supersaturation associates with rising stone risk. Calcium oxalate and calcium phosphate supersaturations rise smoothly with urine calciumleaving no doubt that urine calcium raises risk of calcium stones via increasing supersaturation.

Many calcium stones form on plaque, tissue deposits of calcium phosphate crystals in human renal papillae. Plaque abundance rises with urine calcium excretion, and a plausible theory, vas washdown, links them.

Idiopathic hypercalciuria is Hereditary

FAMILIAL NATURE OF IHFamily Studies

I am not sure if we were the first, but here is our evidence from 1979. 

The arrows point to the stone formers whose families we studied. Filled symbols are men (square) and women (circles) with IH,  asterisks mark children, open symbols did not have IH, and dashed people are deceased. About 50% of immediate blood relatives had IH, in successive generations. Others have also found IH heritable.

IH might look like a simple dominant trait from one abnormal gene, but it results from a number of genes. Incidentally, urine calcium is not the only stone forming trait that appears genetic. Urine citrate appears to be, as well.

Animals

Dr. David Bushinsky bred rats with the highest calcium excretions. Urine calcium rose for the first 40 generations, and thereafter seems at a near plateau. So the trait is breedable.

ghs uca progression-14-07-25 c

These animals form calcium stones and develop a more severe bone disease than normal rats if diet calcium is not ample. So they well mimic human IH.

We humans did not breed ourselves for IH. Something about the trait must have conferred a benefit during evolutionary time.

Children

We had the opportunity to collect 24 hour urine samples from large numbers of boys and girls who were brothers and sisters of children with kidney stones, and also from children in families where none of the children, their parents, or other relatives were known to form stones.

Urine calcium excretions of siblings with more than two stones (left panel of the figure) are highest – farthest to the right. Next highest – second from the right – were siblings with 1 – 2 stones. Siblings with no stones were even lower, third from the far right.

Children from families with no kidney stone history were lowest – most leftward – and almost none had above 200 mg/day of urine calcium loss.

The four bars in the right hand graph say the very same thing. Mean values of urine calcium, shown by the top of each bar, rose progressively with stones.

This is expected if IH is genetic and causes calcium stones.

Hypercalciuria with Hematuria

Hypercalciuria in children not rarely causes hematuria found on routine screening. Loin pain with hematuria is a common syndrome ascribed to crystal passage. IH can raise urine supersaturation and higher supersaturations promote crystals. Hematuria can be familial because it is due to IH and crystals or stones. In adults, unlike children, hematuria can be from malignancy so proper evaluation, even in stone formers, requires imaging and considerable care. 

Bone Disease

There Is Bone Disease in Stone Formers

Epidemiology of Fractures

This figure, from people living in Rochester, Minnesota, shows the cumulative incidence of vertebral fractures among those who had a symptomatic stone (irregular line) and the expected fracture rate nihms271156f1 bone fractures in stone formersbased on the entire population (the smooth line) between 1950 and 1974. The excess of fractures was not observed for hip or forearm.

Bone Mineral Density

Reduced bone mineral density is a general finding in stone formers. Table from Sakhaee paper on bone

Among 2,052 patients assembled from 20 separate studies, between 31% and 65% had some reduction of bone mineral density (Table). Although not remarkable for fractures in the Rochester study, the radius was most affected.

The authors of this review did not conclude that IH caused the low bone density of stone formers. I infer it played an important role, however, because IH can promote bone mineral loss (detailed in the next section) and thiazide diuretics – well known to lower urine calcium in IH – appear to reduce bone disease.

Prospective Bone Mineral Observations

ASPLIN BMD VS UCA

Another reason I make this inference is that the magnitude of urine calcium loss predicts future loss of bone mineral. 

We measured bone mineral density in a number of stone formers with IH, collected 24 hour urine samples, and then re-measured bone mineral density three years later.

When change in bone mineral by three years (vertical axis) is plotted against the urine calcium loss at time 0, (horizontal axis), the trend – highlighted by 68% containment ellipses – points downward: More urine calcium loss at the beginning, more bone loss by three years. A majority of people with urine calcium above 200 mg/d lost bone mineral over three years, whereas those with values below 200 mg/d tended to gain bone mineral.

How Does IH Raise Urine Calcium?

The Extra Calcium Can Come From Diet

qplot of percent calcium absorption IH and N from balance plots for gibbs lecture control file using balance data file in CKD ca and p balances folder

In the balance studies from which I derived normal calcium excretions, scientists fed subjects a fixed diet and measured all food calcium eaten and all calcium lost in the stool. The difference between calcium eaten and calcium lost in the stool is net calcium absorbed into the blood.

Typically measurements are made in 6 day blocks after a few days to equilibrate with the diet, so subjects participate for perhaps 8 – 10 days. I have aggregated the calcium absorption measurements that match the urine calcium excretions I already showed you.

Normal men and women (orange) absorb about 18% of diet calcium. I combined the sexes because they have almost identical values. Women and men with IH – the blue curve – absorb much more calcium, about 30%.

You might ask how calcium absorption can be negative – points to the left of the vertical 0 absorption line. It is because salivary glands, pancreas, liver via the bile, and perhaps the ileum secrete calcium from blood back into the bowel lumen. When diet calcium is less than this ‘endogenous secretion’, stool calcium loss exceeds what is eaten.

An early theory held that IH arose from over absorption of diet calcium: High absorption, more calcium comes into the blood, the kidneys lose it – done. This theory led to decades of low calcium diet as a treatment for stones. No one knew such diets might cause fractures.

The Extra Calcium Can Come From Bone

A Glucose Load Causes Bone Mineral Loss

Years ago Dr Jack Lemann did this informative study. He measured urine calcium excretion (vertical axis) then gave glucose or sucrose (table sugar) to normal people, calcium stone formers, and relatives of calcium stone formers.

jack NEJM pictureCompare the control (left of the big arrows) calcium excretions of the normal subjects to the stone formers: 5 of the stone formers have control values above all but the highest normals. The relatives of stone formers are even higher – and this is fasting, before the sugar load!

Each period was 20 minutes, so this experiment went on for 2 hours. The higher urine calcium with sugar must come from bone – there was no calcium in the sugar drink. It came from bone in normal people and in those with IH but the latter lost far more calcium than the former. Though fasting they had higher urine calcium losses.

In a separate experiment, Lemann proved that the kidneys themselves caused calcium loss from sugar by reducing their conservation of the calcium they had filtered out of blood.

Low Calcium Diet Causes Bone Mineral Loss

We persuaded nine normal people and 27 stone formers with IH to eat a very low calcium diet – 2 mg/kg body weight – for 9 days, and on days 7-9 we collected 24 hour urine samples and measured lcd picturecalcium losses.

The diet went well; most people ate what we asked (middle panel). The normals (the 9 people to the left on the plot) lost in their urine less than 2 mg/kg of calcium daily – lower panel, to the left, so the difference each day between what they ate and lost was positive (upper panel, all normal points were above 0).

The patients were different. Many lost more calcium in their urine than they ate, and did so most of the time. This was bone mineral lost in the urine.

On such a low intake surely everyone was losing bone mineral because the fraction of diet calcium that is absorbed into the blood is far below 100%. I just showed you that it is about 18% in normal people and 30% for people with IH.

But those with IH were more flagrant than the normals. Because their urine contained more calcium than they ate we could prove bone mineral was lost.

In IH Urine Calcium Usually Exceeds Net Calcium Absorbed

On the horizontal axis of this figure, calcium absorption is the difference between calcium eaten and lost in the stool. Urine calcium is on the vertical axis. People with IH are red large dots, and normal people are blue microdots.

Each point compares calcium absorbed in a day to calcium lost in the urine. If urine calcium is higher than calcium absorbed (points to the left of the diagonal line of identity), bone mineral is being lost in the urine. Those to the right the opposite – bone is gaining mineral.

At a net calcium absorption of 150 mg/d or more, a majority of the normal points lie to the right of the diagonal line – urine calcium is less than calcium absorbed. Bone mineral is stable or increasing.

Idiopathic hypercalciuria points all lie left of the diagonal line, negative bone mineral balance, until net absorption rises over 300 mg/d. It takes a huge amount of calcium absorption to overcome the tendency of IH people to lose bone mineral.

Bone Calcium Retention vs. Diet Calcium

Perhaps a more practical way to envision these balance data is to plot calcium retention – net calcium absorbed minus urine calcium excreted – against diet calcium intake.

At diet calcium intakes above 500 mg/day, the average retention (the jiggly blue line) for normals passes through 0, meaning that their bone mineral stores will, an average, be stable. Higher calcium intakes make the normal average rise so that by 1,000 mg/day retention vs calcium intake in mg per day with smoother means red is IH blue is normalsa majority of normal points are above 0.

Among the IH subjects (red), retention rises with diet calcium intake, but the average – red line – never passes through 0. Some points do lie above 0, meaning that not all IH subjects will share the general high risk of bone mineral loss, just as some normal points lie below 0 even at high calcium intakes. But on average, at all reasonable calcium intakes, IH appears to hamper bone mineral retention.

What Have We Learned?

Low calcium diet is not ideal for normal people and a disaster for those with IH. Given IH, even a liberal calcium intake will not achieve stable bone mineral balance for the average person.

These balance data lay latent in papers published from 1900 through until even recent times. Using a different and sophisticated way to assess bone mineral balance, Lieberman and his colleagues showed as early as 1965 that IH reduced bone mineral stability. Yet low calcium diets remained a common treatment for stone disease for more than a decade thereafter.

IH Kidneys Release Excess Calcium 

Filtered Calcium

Calcium gets into the nephrons of the kidneys by filtration from blood. If you do not know about filtration, use this link to learn about it. 

Each of the 2 million nephron units we possess in our two kidneys has a glomerular filter that filters water, sodium, calcium, phosphate, oxalate, and thousands of other small molecules and ions out of blood into the long tubules that process the filtrate into urine. 

Reclaimed Calcium

The process we care about here is reclaiming filtered calcium back into the blood. Normal people excrete about 2% or less of filtered calcium, those with IH excrete 4% to 5% or more.

Here are a few numbers. We filter about 150 liters/d. The filtrate contains about 40 mg/l of calcium: 40×150 = 6,000 mg/d of calcium. Of that 2% is 120 mg/d, 4% is 240 mg/d, 5% is 300 mg/d. So the differences in percent excreted account for the range of calcium between normals and stone formers.

Where Along the Tubule?

Review the Proximal and Distal Tubules

Each kidney tubule resembles a woman’s hair – long as a long hair, and that thin. Down the center of the hair is its lumen through which the filtrate passes to become urine, and where calcium is reclaimed.

Go back to the filtration article and check out the tubule picture. Pay special attention to the proximal tubule. In the proximal tubule calcium is reclaimed in parallel with sodium. In the distal tubule – on the picture in the link – calcium can be reclaimed independent of sodium.

Urine Calcium Follows Urine Sodium

This picture illustrates the basis for recommending a low sodium diet to lower urine calcium in IH.

It shows how urine calcium (vertical axis) rises as urine sodium (horizontal axis) rises. The rise is far steeper among stone formers with IH (blue) than in normal people (red). Circles show experiments – diet sodium was deliberately altered. Triangles show observations – diet sodium and urine calcium varied on their own.

Urine Calcium and Sodium are Linked in the Proximal Tubule

As you eat more sodium, urine sodium goes up so output balances intake. One way the kidney accomplishes this balance is that filtration rises with higher sodium intake. Another is that reclamation of water and sodium in the proximal tubule (the part nearest the glomerular filter) goes down – more sodium and water flow downstream in the nephron. Calcium goes with it, the two are linked by the way that part of the nephron works.

For this reason, the steeper slope of urine calcium vs. urine sodium in IH must arise from abnormalities further downstream from the proximal tubule. We cannot presently identify where or how this happens.

What Can We Do With What we Know?

We can shut down filtration and increase reclamation of sodium in the proximal tubule. Both will reduce urine calcium by reducing delivery of calcium downstream. Lowering diet sodium does both, reduces filtration and increases proximal tubule sodium reclamation. The latter is usually more prominent than the former.

Thiazide diuretics do the same. They increase reclamation in the proximal tubule.

Once you understand this, you understand why reducing diet sodium and taking thiazide are two ways to do one thing. So the more you limit diet sodium the less you need thiazide, or at least the less dosage you need. On the other hand, if you take thiazide and eat a lot of sodium, the sodium will undo the effect of the drug.

What Happens to Bone?

Diet Calcium Must Be High

All this gives some insight into why IH appears to reduce bone mineral.

When we eat, the kidneys release calcium into the urine, normals and IH alike. But IH patients release a lot more calcium, depending on their sodium intake. If the diet has adequate calcium in it, bone can get its share even if more than normal is lost in the urine. If the diet is not so adequate, less than 1,000 mg/d, bone may not get its share even in normal people. Given IH, diet calcium must be quite high, at least 1,000 to 1,200 mg. But that cannot be sufficient as I have shown you. Even at such high calcium intakes, bone balance in IH is usually negative.

Diet Sodium Must be Low

The only present remedy for renal calcium wasting in IH is to lower delivery out of the proximal tubule. Low diet sodium, thiazide, ot both can do it. We presently have no other means that have proven effective.

The Combination of High Diet Calcium and Low Diet Sodium Can Preserve Bone Mineral

The best proof of this is one study showing that in perimenopausal women the combination of low diet sodium and high diet calcium can promote bone mineral gain. 

The women each ate all four of the diets shown along the horizontal axis: high and low calcium (Ca) and sodium (Na). Specifically, the sodium levels were 1600 and  4400 mg/day, and low and high calcium (518 and 1284 mg/day. 

On the vertical axis is calcium in mg/d. The colors say if ‘calcium’ on the vertical axis is calcium absorbed (blue), secreted by the GI tract (red), lost in urine (gray), and bone balance (black).

Low calcium diets were hopeless. High calcium diets with high sodium led to high absorbed calcium (blue) but also high urine and GI endogenous secretion losses (‘ENDOFEC’): red and gray bars point downward. Reducing diet sodium lowered the urine loss (gray bar was less down) and also – surprise – less GI calcium secretion (red bar is less down).

The net result is good for bone. This one combination drove bone mineral balance positive (Black bar above 0). 

Before we leave this powerful demonstration, look back on urine calcium (gray bars). The high calcium low sodium diet gave the very same urine calcium as the low calcium high sodium diet. In other words, the women could raise their diet calcium from 500 to nearly 1300 mg/day and yet by lowering diet sodium to 1600 mg/day keep urine calcium unchanged.

What Makes Calcium Go In or Out of Bone?

Blood is saturated with respect to the initial phases of bone mineral, so called early hydroxyapatite forms. Likewise bone has considerable circulation, so that the outer layers of bone can be in physicochemical equilibrium with the blood. In isolated bone reduction of calcium phosphate supersaturation leads to physical dissolution of bone mineral.

It seems not unreasonable that tiny reductions in blood calcium phosphate saturation can occur when kidneys release calcium into the urine at a rate that exceeds diet calcium absorption. The loss of bone mineral from simple sugar ingestion may well be an example of this effect. Of course bone is regulated by myriads of hormone signallers, but short term mineral balance could be affected by physical forces. This is an area that deserves research.

I should say that in presenting this conjecture about bone it is just that. Furthermore I doubt it is sufficient as an explanation. But it shows at least one plausible connection that can be demonstrated in isolated bone, and perhaps in humans.

In another article, as yet unwritten, I will take up the larger issues of bone and kidney in IH, and show the deeper science that is now available.

What Should We Do?

Kidney Stone Prevention

Without doubt, reduced diet sodium and refined sugar are valuable in all people with IH. Although I did not demonstrate it here, a high diet protein load raises urine calcium and is best brought into the normal range of 0.8 – 1 gm protein/kg body weight/d. Protein intake is calculated from urine urea excretion as the protein catabolic rate (PCR) and best quality kidney stone testing vendors present it on reports.

Bone Disease

Provide Adequate Diet Calcium

Diet calcium must be adequate, 1,000 to 1,200 mg/d. Without concomitant control of diet sodium this alone would raise urine calcium and kidney stone risk. But when combined with low sodium it will not. Multiple proofs of this statement exist. I just showed you one in the lovely four way bone experiment.

Measure Bone Mineral Density

US insurance practices exclude bone evaluation in large swathes of stone forming populations. But bone mineral scans are not very expensive compared to the eventual costs of fractures. A useful medical buying guide places the bone mineral density scan cost to uninsured people at about $200.00, and mentions that in May prices can be lower because it is national osteoporosis month. The price usually includes a simple medical interpretation.

The Kidney Stone Diet

The proper diet for prevention of the common calcium stone arises almost totally from the requirements to treat IH: reduced diet sodium, refined sugar, and protein, and adequate calcium for bone. The last of these, high diet calcium plays another role in stone prevention by lowering urine oxalate. That is fully described in other articles

As well as stone prevention and the protection of bone, this diet is thought beneficial for reduced risk of hypertension and vascular disease, to which stone formers seem unduly prone. 

Because it accords with general diet recommendations for the entire US population, I can recommend its use without hesitancy for stone formers and, incidentally, all the rest of us, too. 

173 Responses to “IDIOPATHIC HYPERCALCIURIA (IH)”

  1. Billy Gibson

    Hi Dr. Coe,
    Along with everyone else here – thanks for your valuable insights. I am hoping you can shed some light on my situation.

    I am in my 60’s, in good health, physically fit, proper weight and I lead an active lifestyle. I’ve had a number of calcium oxalate stones in the past 5 years – some have apparently passed and some were surgically removed. I was diagnosed with hypercalciuria and put on a dietetic a month ago. I was told that my kidneys are leaking calcium, and that diet alone would not address my problem. Here some key values from recent labs:
    Urine Calcium: 350
    Urine Oxelate: 34
    SS CAP: 2.10
    Urine pH: 6.5
    Na 24: 64
    Ca 24/Kg: 4.6
    Ca 24/Cr 24: 232

    The dietetic has the bad side effect of waking me up to use the bathroom every 60 minutes at night. I am on the minimum dose of chlorthalidone, so reducing dose is probably not the answer. I have the discipline to maintain a specific diet, and would be happy to do so as a long term fix, but I am uncertain if this would work for me. I would like to know if the lab numbers offered above indicate a case where diet would have no significant effect, and therefore living with the diuretic is the way to go.

    I’ll add that my Doc is running the required potassium test today (it’s been a month) and will also look at parathyroid hormone, so maybe we’ll discover something there.

    Again, I look forward to your thoughts on my case.
    Thanks!

    Reply
    • Fredric L Coe, MD

      Hi Billy, Your urine calcium is very high despite a very low urine sodium of 64 mEq/d and chlorthalidone as well. I presume your serum calcium is perfectly normal, and your PTH is not suppressed below normal. Such a high calcium with so low a diet sodium and CTD is very unusual and points to alternatives to common idiopathic hypercalciuria. Your physician is right to measure PTH, she/he might want to measure 1,25d as well. Regards, Fred Coe

      Reply
      • Billy Gibson

        Thanks for the response Dr. Coe!

        First off, sorry for my consistent misspelling of “diuretic”!
        I just got my latest blood panel labs back and here are key results relevant to the conversation so far…
        PTH 31 pg/ml
        Sodium 138 mmol/L
        Potassium 3.8 mmol/L
        Calcium 9.4 mg/dL

        The only item in the full panel not tagged as “normal” is glucose at 107 ml/dL, but I wasn’t fasting (wasn’t told to!) and as far as I can tell, 107 is ok if the patient is not fasting. Otherwise everything is a-ok.

        The only clarification that I’d make is that I wasn’t taking any diuretic at the time of the 24-hour urine test, so the results in my initial post were from before I was taking a diuretic. Not sure if that matters to what you are thinking.

        Your comment “Such a high calcium with so low a diet sodium and CTD is very unusual and points to alternatives to common idiopathic hypercalciuria” I took to mean that idiopathic hypercalciuria is not a likely an accurate diagnosis for me, is that correct? If so, are there likely avenues for me to look into with my Doc?

        Reply
        • Fredric L Coe, MD

          Hi, I should perhaps say better that such high values do occur in IH but are very uncommon. That your PTH is not suppressed removes one category of unusual hypercalciuria. I have to assume fasting serum calcium is absolutely normal – be sure it is. Perhaps your 1.25 vitamin D is very high, a known driver of very high urine calcium levels. If it is IH with very high urine calcium despite moderate diet sodium, the only reasonable approach is to limit diet sodium as much as possible – usually 1500 mg is ideal, or even lower – and use thiazide type diuretics in that order. Perhaps your person physician has already thought much the same. Fred

          Reply

Leave a Reply