IDIOPATHIC HYPERCALCIURIA (IH)

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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.

I have found that patients will change their diets and take medications only if they fully understand why such measures are likely to benefit them. That is why I have written this article.

Why The Bathers?

I placed the bathers here because nothing seems so fit a metaphor as bathing for an explication of IH. To me, bone is like the bather in a bathtub, the flow of in from faucets and out in the drain like the GUT and the kidneys that engage each other in regulating the net balance calcium through the body.

The Large Bathers (1884-87) of Renoir and The Large Bathers (1900-1906) of Paul Cézanne both reside in the Philadelphia Museum of Art (This will not render properly on a pad or cell!), and I had trouble deciding which to choose.

Surrounded by gardens toward the end of summer I chose the beguiling Renoir. In winter, the gray stones of our university might have favored the dark and brooding figures of Cézanne.

What is Idiopathic Hypercalciuria?

As hypertension is defined by pressures that associate with harm – stroke, heart failure, heart attack, urine calcium is ‘high’ when it associates with stones.

What is Hypercalciuria?

I have already shown you Curhan’s results linking urine calcium losses to risk of stone disease. For two cohorts of women – red – and one of men – blue – increasing levels of urine calcium – shown along the horizontal axis in six bins – go with increasing risk of becoming a kidneyPQ RISK VS URINE CALCIUM LOW AND MEAN OVERPLOTTED.jpg stone former (Relative risk, on the vertical axis). A risk of 1 means no higher than among people with urine calcium below 100 mg/day – the reference population.

The average, or mean risk for forming a stone, is at the top of each bar, which is plotted from a base of 1 (the dashed line). The lower 95th percentile of risk is at the end of the solid bars which are also plotted up from one.

When the bottom of the 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.

As the urine calcium rises, risk – top of the bar – rises in smooth progression. As higher blood pressures predict more risk of strokes, higher urine calcium predicts more risk of stones.

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

What Does ‘Idiopathic’ Mean?

Many diseases can raise urine calcium excretion, but among hypercalciuric stone formers the vast and overwhelming majority have none of these diseases. Their urine calcium exceeds 200 mg/d for no obvious reason – idiopathic, arising of itself, without overt cause.

Normal Calcium Excretion

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 from normal adult men (blue) and women (red) published as a collection nowhere else.

normal uca male anf female.pngThe Curhan demarcator – 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. Like high blood pressure high urine calcium confers risk, but risk does not always culminate in disease.

The 95th percentiles of these distributions, at about 275 and 325 mg/d of calcium for women and men, once defined ‘high’ urine calcium. That is statistically rational.

But like old definitions of ‘high’ blood pressure (160/90), these limits greatly underestimated risk of disease. I renounce criteria not long ago promoted by my colleagues and I: >250 mg/day women, >300 mg/day men, >4 mg/kg body weight either sex, 140 mg of urine calcium/gm urine creatinine.

No doubt they confer risk of stone, given the Curhan demarcator. But they are too high and we should abandon them for clinical use.

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 from 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

Family Studies

FAMILIAL NATURE OF IHI am not sure if we were the first, but here is our evidence from 1979. 

The arrows point to stone formers, filled symbols are men (square) and women (circles) with IH, * are children, and dashed people are deceased. In the 9 families IH was about 50% prevalent. Many others have found IH heritable.

It is not likely to be a simple trait from one abnormal gene, but some outcome of a number of genes. As this reference mentions, urine calcium is not the only stone forming trait that appears genetic; urine citrate appears to be, as well.

Animals

Dr. David Bushinsky, in decades of outstanding research, has proven that rats can be bred for what appears to be a rather close match to human IH. His strategy was to breed rats with the highest calcium excretion, and continue doing this for generations.

What attracts my notice is the progression over the generations. For the first 40 generations, urine calcium rises almost linearly. Thereafter, it is at a near plateau, more or less.

Forty generations!

ghs uca progression-14-07-25 cAmong humans that is 800 years taking 20 years for a generation, and in fact that is a skimpy generation time for us.

Yet, if we think about the matter, 800 years is nothing in evolutionary time. Even his outermost generation, near 100, or 2,000 years, is nothing as against evolution. So I am satisfied that IH is breedable in animals, and could have easily arisen in us as a response to evolutionary pressures. What those pressures might have been is not a topic for here.

I cannot pass by this heroic accomplishment without a pause, and some stirring of admiration and sense of accomplishment. How brave to have started this, and how persevering and accurate to maintain these generations intact and continuing. How productive, too.

Of importance here, these animals form calcium stones and develop a far more severe bone disease than normals if diet calcium is not ample.

Children

Some years ago we had the opportunity to collect 24 hour urine samples on large numbers of boys and girls who were brothers and sisters of children with kidney stones, and 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 are farthest to the right – highest in the left panel. Next highest – second from the far 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 idiopathic hypercalciuria is genetic and causes calcium stones.

Hematuria

Hypercalciuria in children not rarely causes hematuria found on routine screening. Loin pain with hematuria is a common syndromic epithet, ascribed to crystals because 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. 

IH Is Not the Only Reason Stones Are Familial

I will not pursue the matter here, but stones themselves are familial, presumably hereditary, and not always because of IH.

Bone Disease

There Is Bone Disease

An outstanding scientist in the kidney stone field, Dr. Khashayar Sakhaee, has authored a superb review of the bone problem of stone formers. This figure, from a prior study of people living in Rochester, Minnesota, shows the cumulative incidence of vertebral fractures among people who had a symptomatic stone (irregular line) and the expected rate ofnihms271156f1 bone fractures in stone formers fractures based on the entire population (the smooth line) between 1950 and 1974. The excess of fractures was not observed for hip or forearm.

The review collates 20 studies that concern bone mineral density mostly in relation to idiopathic hypercalciuria in stone formers. The broad message is a reduced level of bone mineral as a general finding, observed by many independent investigators using a variety of instruments to assess the bone. One cannot escape the conclusion that among stone formers, most of whom are described as having IH, bone mineral is reduced as a rule.

The authors summarize their wide ranging literature review in a little table I find irresistible. Among 2,052 patients reviewed, between 31 and 65% (939 patients) had some reduction of bone mineral density.

Furthermore, the radius, a site not remarkable for fractures in the Rochester study, is most affected with regard to reduced bone mineral density.

Table from Sakhaee paper on boneWe have shown that the magnitude of IH 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.

As a group, the net change in bone mineral density of femoral neck (left panel) and spine (right panel) centered around 0. You can see this because the points more or less fall equally above and below the horizontal line at 0 change.

But when change in bone mineral is plotted against the urine calcium loss (horizontal axis), the change over time is negative – the ellipses slope downward. ASPLIN BMD VS UCAPeople with higher urine calcium loss lost bone.

IH Seems A Factor in the Bone Disease of Stone Formers

Risk of stones begins at about 200 mg/day, and risk of bone disease seems to follow having stones. It is interesting that most points below 200 mg/d on the figures show an increase in bone mineral, most at above 200 mg/d show a decrease.

Although Sakhaee is careful to point out that bone disease associates with stone disease, IH is obviously a prominent issue in his review, and many of the studies of bone disease in stone formers have centered on IH as a causal factor. I suspect the association is stronger than it might seem because IH itself has been diagnosed variably over the 20th century, often using urine calcium criteria far above those needed to increase stone risk.

So What?

Every stone clinic is a bone clinic. All stone formers deserve a bone mineral scan.

Dr. Sakhaee points out that 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.

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 – the curve on the adjacent quantile plot combines adult men and women who in fact display identical behavior. People with IH – the blue curve – absorb much more calcium, about 30%.

You might ask how one gets negative absorptions – points to the left of the vertical 0 absorption line. It is because pancreas, duodenum, and perhaps ileum all can 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 of IH was over absorption: 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. No one knew such diets might cause fractures.

The Extra Calcium Can Come From Bone

A Glucose Load Can Raise Urine Calcium

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 pictureLook at the control calcium excretions of the two right hand groups: 5 or so of the stone patients have control values above all but the highest normals; the relatives 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 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.

In a separate experiment, Lemann proved that the loss of extra calcium from sugar was because kidneys reduced their calcium conservation, they permitted an increase of urine calcium.

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 sets of points left of the space) 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, points above 0).

The patients were different. They 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

I already showed you calcium absorption as determined by the difference between calcium eaten and lost in the stool.

In this plot, IH is in red large dots, and normals in blue microdots. Net calcium absorbed is on the horizontal axis, and urine calcium is plotted against net absorption on the vertical axis. Points to the left of the diagonal line of identity mean urine calcium exceeds what was absorbed – negative calcium absorption.

At a net calcium absorption of 100 mg/d or more, a majority of the normal points are to the right of the diagonal line – urine calcium is less than calcium absorbed. Bone mineral is stable or increasing.

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

Bone Calcium Retention vs. Diet Calcium

Here, I plot the net calcium retention – net calcium absorbed minus urine calcium excreted against the calcium eaten for all the people with IH (red) and normal people (Blue) who had balance data in my collection.

At diet calcium intakes above 500 mg/day, the average retention (the jiggly blue line) for normals is about 0, meaning that normals in general will have stable bone mineral stores. Higher intakes make the average rise above 0 and at about 1000 mg/day or so, a common nutritional goal, a majority of normal points are above 0.

retention vs calcium intake in mg per day with smoother means red is IH blue is normalsFor the IH subjects (red), retention rises slowly with diet calcium intake, but the average never reaches 0. Some points 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.

What Have We Learned?

The message is that low calcium diet is not ideal for the normal population and a disaster for people with IH. But even with a liberal calcium diet IH makes it hard to bring bone mineral into balance which is probably why there is a bone disease.

Using sophisticated measurements of bone mineral turnover, Lieberman and his colleagues showed as early as 1965 that patients with IH had something very abnormal about bone. Low calcium diets remained a common treatment for stone disease for more than a decade later.

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. In normal people about 98% or more filtered is reclaimed, in IH it is less, about 95 – 96%. Not a lot, you think. 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 that ‘little’ difference accounts 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 single woman’s hair – long hair, that thin. Down the center 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 is reclaimed independent of sodium.

Urine Calcium Follows Urine Sodium

This picture is 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 more obvious among stone formers with IH than in normal people.

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.

Why Does Urine Calcium Rise More in IH than in Normals as Urine Sodium Rises?

It must be downstream of the proximal tubule, because sodium and calcium are reabsorbed together there. Where is not easy say. Calcium and sodium reclamation can differ at multiple places downstream from the proximal tubule, and which ones cause the higher slope in IH is not known.

What Can We Do With What we Know?

We can shut down filtration and increase reclamation, and that is what low diet sodium does. That is what the graph shows us.

Likewise, the thiazide diuretics do the same. We have proven they increase reclamation in the proximal tubuleOnce 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.

We can take potassium citrate or increase diet potassium alkali with fruits and veggies. At least the potassium citrate does in fact lower urine calcium at any given sodium intake. 

What Happens to Bone?

I think it is this way. 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 1000 mg/d, bone may not get its share, especially when IH is present.

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

What is the Final Word?

Stone formers tend to have IH. For them reduced diet sodium combined with high diet calcium is a reasonable way to live. It reduces urine calcium and protects against bone loss. Thiazide is a fine stone prevention drug, but it is just another – and lesser if more convenient – way to do what reduced diet sodium will do. For a stone former, the diet is best for the whole family, because IH is inherited.

148 Responses to “IDIOPATHIC HYPERCALCIURIA (IH)”

  1. Rose Marie Murray

    Correction: I miscalculated my husband’s daily calcium intake. Instead of approximately 1000mg/day, it is closer to 550mg/day. My apologies. Rose Marie

    Reply
  2. Rose Marie Murray RD

    Hi Dr. Coe,

    Thank you for providing such valuable information and for offering this opportunity to ask for your advice! I hope this isn’t too much information, but I would greatly appreciate your in-put

    My husband (54 yrs old) had his first (and hopefully last) kidney stone October 31, 2019. After reading extensively on your website, I assume that he has idiopathic hypercalciurea. He has been eating a lot of sodium. It makes sense.

    I understand your dietary advice: sodium 1500-2300mg/day, Calcium 1000-1200mg/day, protein .8-1.2g/kg body wt /day, water 3 L.

    My question is to ask for clarification of your oxalate recommendation of 100mg/day for stone formers. How do I put that into perspective with the fact that his urine oxalate levels were normal (but he had been eating high oxalate prior to the stone, and then very low oxalate after the stone bc/ it was an oxalate stone) and his calcium intake meets your recommendation? Should he still try to keep dietary oxalate to 2300mg Na/day. He eats 1.1-1.5g protein/kg body weight /day.

    Reply
    • Fredric L Coe

      Hi Rose Marie, You are wise and shrewd. If his urine oxalate is normal then he is done with the oxalate diet apart from the worst foods – spinach and rhubarb, and lots of nuts, pepper, and dark chocolate. With high diet calcium from food distributed to the main meals oxalate is a minor player in people with low values of urine oxalate as you describe. The big problem is to keep the sodium low enough that his urine calcium is not too high- -so measurements are needed. Be sure everything has been measured and attended to – here is a good overview. Regards, Fred Coe

      Reply
      • Rose Marie Murray

        Thank you so very much for your response and advice. We’ll focus on lower sodium, higher calcium per your recommendations and then re-do the 24 hr urine in a couple of months.
        Best, Rose Marie

        Reply

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