MIDDLE AGE AND KIDNEY STONES? WHY NOW?

Middle age 45 – 65, not the usual time to form your first kidney stone. The average for new stone onset is 35, with a spread of about 12 years, so by 45 you might think the odds are in your favor. But not always. Sometimes they start late, even into your fifties or sixties. It doesn’t matter some of the time. A stone is a stone. But older people get stones for a different spectrum of reasons than when young, so you have to think a bit about why.

The image, a self portrait by Jan van Eyck (1390-1441), was painted in 1433 in oil on panel. It hangs in the National Gallery, London.

This article is co-authored by me with Jill, but was her choice of topic. She is sure her patients will love it. I hope so.

Primary Hyperparathyroidism

This is not rare as a cause of stones, and very important. On the one hand, it is a systemic disease. High serum calcium can cause kidney injury, and raise blood pressure. Bone mineral can be lost. On the other hand, it is curable. Although PHPT can occur in youth, the average age of diagnosis in a recent and large VA hospital record review was 67-68. A large Canadian survey of published papers estimates that diagnosis is usually after 50 years old and that, as is well known, women have it more frequently than men. In a large single center report of a university cohort the mean age at diagnosis was 61 years with stones, 69 without stones.

We have already written two articles on how PHPT works, and how it is diagnosed and treated. This one is very clinical. This one is very detailed, all about mechanisms and for the curious. What matters here is that if your stones begin later in life – after 50, for example, this disease needs to be higher on your list than if they begin at 25 or 30. You need to be sure about your serum calcium. You need to be sure it is measured when fasting, and looked at carefully. Even a little elevation should raise an eyebrow and lead to more measurements to be sure. 

Uric Acid Stones

When Do They Occur

This nifty figure from a paper by the Mayo Clinic group shows how age changes stone type. Men are on top. Calcium oxalate stones are always the most common, in both sexes, but under age 30 or so calcium phosphate stones (the open squares) are reasonably common, especially in women.

Uric acid stones, the open diamond, creep up on both sexes, after age 40 in men, and 50 in women, and by the sixties are more common than calcium phosphate stones in either sex.

Uric acid stones occur because the urine pH falls, we know that with perfect certainty. The low pH protonates the uric acid molecule, so it loses its only charged site. Water no longer has a good way to connect with it, so it just leaves the solution as crystals.

Why Does the pH Fall?

We asked ourselves that very question and tried to find out.

Lots of things happen as we get older. We get fat. Our kidneys gradually lose their youthful glow. Both of these can lower the urine pH. We get diabetic, and that surely lowers urine pH. Do any of these account for what this figure shows us?

Urine pH Does Indeed Fall

We were fortunate to come into possession of a large set of laboratory data collected by a national kidney stone testing laboratory. It has no names, but did have age and sex, and urine stone risk factors. So we could reconstruct what happened to urine pH with age in men and women.

In both, men are triangles, urine pH fell very rapidly beginning below age 30, and at all times women had a higher pH than men. We have already written about this feature of women. Eating exactly the same food as men, women extract more alkali from it, so their urine is more alkaline. That is why they form more calcium phosphate stones, as the picture from Mayo Clinic shows.

But something happens to women as they age, and men, too. Whatever it is that makes their urine rather alkaline at the beginning gives way with age, and not so old an age, either. After all, much of the fall is before 50, the early part of so called middle age.

It Is Not The Getting Fatter

We get fatter with age. Everyone knows that. Not everyone does it, but on average we all do. I suppose it is less exercise and too much food, but we are not studying this matter here, now.

Below, you can see body mass index (BMI) rising with age in this very large set of data (nearly 9,000) patient lab

studies. It goes up in men (triangles) and women, and it goes up very rapidly between 33 or younger and 50.

But, if you adjust for the BMI, the urine pH fall is not affected.

The urine pH falls about the same in both sexes. Compare the graph just to your left with the one just above.

By adjusted, we mean we used complex multi-variable models to account for the rise in BMI and the linkage between BMI and urine pH. They are linked, and BMI rises, but the rise is not enough, given the linkage, to explain almost any part of the falling pH. So it is not obesity.

It is Not Loss of Kidney Function

Here is another graph. Kidney function was measured using creatinine clearance, a common measure.

It went down with age.

But, it began to fall after urine pH had already fallen quite a bit. In other words, the one was not correlated with the other very well. Correlation is not causation, but the other way around is true. Things that are not correlated are not often related causally.

A more elegant approach is to do another of the multi-variable analyses, which we did. The graph on the right, just above, shows that urine pH fell more or less the same if you did (as here) or did not (the original graph above) adjust for kidney function. So, it is not BMI and not kidney function.

pH Falls Even Though Alkali Absorption Rises

The reason for the higher urine pH in women is their greater ability to absorb alkali from their diet. So, was it possible that with age people lost some of that ability? Their bodies would have less alkali from food, and their kidneys would have to work harder excreting acid, and make the urine more acid in the process.

What we found was the exact opposite. The absorption of alkali, which is called GI anion for historical reasons, rises with age. It does so in women and in men. When women are younger, they absorb more than men. See how the circles, women, are higher than the triangles. But around 50 or so women and men converge because women are rising slowly, men rapidly.

But all the while, urine pH is falling. That is backward. When we showed you how women act, you could see that with each meal their GI anion rose and their urine pH rose with it. Here, the urine pH is falling despite more alkali.

You might ask what would happen if we used our multi-variable mathematics to remove the effects of the increased GI Anion. How much does it help keep the urine pH from falling even more?

Without The Extra Alkali Urine pH Would Fave Fallen Far More

Here is the calculated effect. Urine pH falls far more and far more steadily, and the sexes are now more or less the same.

We think that the actual losses of kidney function and the rising BMI were always important. But, as these would have tended to make the urine acid, rising GI Anion offset their effects.

If you take it away, admittedly by mere mathematics, you see what would happen if there were no compensation.

Do we really think that somehow the intestines know to raise their absorption of alkali?

Why not?

They have about 10% of all of our neurons, and the brain communicates with the GI tract.

This is all for some future research. But what it tells us is that age itself, for reasons we do not as yet know, lowers urine pH. As a result uric acid stones become far more common, and the phosphate type of stone far less common.

Diabetes and Insulin Resistance

All of the forgoing was a large scale population effect. Within that population were certainly people with diabetes or insulin resistance. They cannot account for what we found because most of the fall in urine pH occurred rather young, at a time when the sheer prevalence of diabetes has not as yet risen so much.

But for many people, particularly those with serious obesity, or simply those over age 50, diabetes and insulin resistance are increasingly common. Both states lower urine pH, a lot, and cause uric acid stones. We have reviewed the main research work on this topic, that was done mainly by our colleagues in Dallas, Texas.

New onset uric acid stones can simply reflect the general age effect. But it may not be that. In the earlier stages of insulin resistance, insulin levels run high and common fasting blood glucose levels remain ‘in the normal range’. Usually they are at the top of the range, and the hemoglobin A1C is too high – 5.9 or more. It is then that one is best off taking steps, like weight loss and major life changes.

You Are Just Late To The Party

Life Has Changed

The onset age for stones may center around 30, but there are those who are slow and wait until later. Perhaps they formed their stones in their 30’s but no one knew. Perhaps they changed something and brought the stone on. Some people begin a busy travel schedule because retired, some take up extreme sports or marathon running to stay young. Some progress at their work and are promoted to a job that requires lots of long distance travel. Lots of people make eating out a time to meet friends and family, because the children are all gone.

You might think this has no special significance, but it may.

More than eating out, people change their diets in mid-life, to be healthier. But the changes may not always be healthy. Fad diet are always like the butler in a murder mystery: present at the scene, and capable of almost anything.

Your Genetic Hypercalciuria Was Unnoticed

If you had genetic hypercalciuria, you would not have known about it. So new stones mean that you need to check for that problem, and also for bone disease.

For men, the association between stones and bone disease is very well documented. For women, at least in a large epidemiological study, a history of stones and finding of reduced bone mineral were not linked. But whether they might be through genetic hypercalciuria could not be ascertained because no urine testing was available.

In studies that specifically focus on stone formers, a link to bone fracture appears far more obvious than in studies that focus on bone mineral loss as a primary aim.

Urine calcium is known to rise with insulin resistance and diabetes. Although we are not convinced about new calcium stone onset, it is enough to mention here that new calcium stones should always lead to at least a brief look at fasting blood glucose.

Drugs

If anyone asked me, I would say Topamax and its many relatives are a common reason for new stones anytime in life. Especially in people with genetic hypercalciuria, new use of calcium supplements can cause stones. There are so many more possibilities we can just say that with new stones you need to review all of your meds and supplements, perhaps especially the latter. Maybe change your diet and stop the Tums for esophageal reflux.

What Does This Mean For You?

New stones in midlife or later mean they must be analysed. This is absolute. Otherwise how can you be sure about uric acid? Primary hyperparathyroidism produces calcium phosphate and calcium oxalate stones. We have always advocated for analysis of every stone, and in later years that maxim is more important than ever. New ones are a worry. But established stone formers can change from calcium to uric acid.

Apart from stone analysis, be sure your fasting blood calcium is truly normal. We mean by this not only within limits but a bit below the very top, because PHPT can raise blood calcium very slightly yet be there and a serious disease. If it is even suspicious, we have already written out what we do, which is to get many more fasting morning bloods for calcium, and with time things will become clear.

Think about your bones and your drugs, and how your life has changed. Think about blood glucose and be sure it is normal.

At the end, you may simply be a late comer. If so, treatment is as it is for everyone. But if not, a serious inquiry may give you real benefits.

 

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