We have known for a long time that phosphate stone formers are mainly women. We also have long known that phosphate stones form when urine is more alkaline, and that women produce a more alkaline urine than men. So the fact of phosphate stones being more in women seemed an obvious consequence of their physiology.
But that is to overlook the obvious. Why do women have this physiology, this alkaline urine? Have it so consistently they form calcium phosphate stones as geological relics?
If asked, most would say women do this because of how they eat.
Compared to men women eat more veggies, a source of alkali, and less meats – a source of acid. More alkali in their diets, a more alkaline urine, phosphate stones, and that was that.
And that was wrong.
Not only wrong, but in being wrong missed a chance to see something really interesting, something perhaps evolution favored because it increased the fitness of our species.
The study, Young Spartans Exercising, by Edgar Degas, hangs in the Art Institute of Chicago. The painting itself hangs in The National Gallery, London. Degas never expressed his own reasons for creating this scene of young women and men exercising together, but the independence of Spartan women is well documented. I put it here because it illustrates one way a culture sought to enhance fitness of the species to increase its chances for successful continuation. Although the London painting is more finished, this one is, to me, more graphic, more vital, more exciting, higher in energy.
Alkaline Urine is the Least of It
When Elaine Worcester and I set out to understand how women produce a more alkaline urine, our intent was, if not modest, certainly circumscribed. One possibility was prevailing opinion: higher urine pH in women was from their diet and when women and men were studied while eating the exact same foods their urine pH values would no longer differ.
It is Not the Food
That possibility was eliminated at the very beginning.
Here are the urine pH values for women (F) and men (M) fasting, fed, and overnight (ON). Fasting, and ON the sexes do not differ. The female bars seem higher but the variation is large (the thin standard error lines). But when they ate, women far exceeded men. This is because the women not only start higher, fasting, but increase their pH when fed whereas men do not increase it.
So food is critical, but the food was the same food. This means that when they eat women extract from their food different proportions of things that regulate urine pH. It is biology, not what they eat, that matters.
What food has that can make urine alkaline is alkali, substances that pose an alkaline load on the body. The kidneys respond to that load by removing the extra alkali, and in the process make the urine more alkaline.
So this one graph, showing the sex difference in pH from eating the same food, tells us that women extract alkali from that food. It is true that the resulting alkaline urine pH predisposes women to calcium phosphate stones. But it is equally true that the extra alkali may be highly beneficial.
What are Alkali?
Like the positive and negative electrodes of a battery, or the north and south poles of a common magnet, acid and alkali are names for opposites, names that may have historical meaning but are, in reality, mere verbal conventions. With apologies beforehand to my acid base colleagues, I offer a simplified image to further my article on women. If what I say is not exact, it is also not wrong.
Protons Personify Acid: pH
Protons – the nuclei of hydrogen atoms – can be viewed as the currency of acid base combination. Protons have a single positive charge. Because their concentration can range very widely, we use logarithms to express it, and call the logarithm pH. If [H+] is the concentration of protons, in water for all of our discussion, pH is the logarithm to the base 10 of 1/[H+], so as pH rises proton concentration is falling.
Acids and Bases Viewed from a Proton Perspective
An acid is a molecule that can donate a proton, a base – or alkali in the plural – is/are molecules that can accept protons.
Right away you can see the relativeness to all this. Consider two acids. One is ‘stronger’, meaning it gives up its proton more readily than the other. So it is an acid, the other of the two is its relative base.
Water Is an Acid and a Base
Since most of what we are is water, we usually speak of being an acid or base in water.
Water is an oxygen atom (Yellow) with two hydrogen atoms (H): H2O. The hydrogen atoms are bonded to the oxygen atom because they share electrons (small circles orbiting the big central nuclei). The hydrogen wants one more electron to fill out its shell, the oxygen wants two more electrons to fill its larger outer shell. They share their electrons and both are happy.
A hydrogen atom without its electrons is the proton I have already spoken about. Being so powerfully charged and small, they hardly exist alone but almost always are found attached to other molecules via charge attraction.
When water gives up a proton we have, instead of H2O, the hydroxyl ion: OH–. The minus sign connotes the loss of a positively charged proton. When water takes up a proton we have H3O+, the hydronium ion, + denoting the extra proton. So, in water, pH really connotes the concentration of the hydronium ion.
A molecule that will take a proton from water can be called a base, or basic or alkali molecule – compared to water, and one that donates a proton to water can be called an acid, or an acidic molecule compared to water.
pH of Water
When pure, water has a pH of 7. Since water is the medium our cells live in, and also the medium of their interiors, we tend to speak of acidic and basic – or alkaline – solutions as below or above pH 7. Our blood pH is 7.41, in health, or slightly alkaline. Urine pH varies from 4.5 to nearly 8, because kidneys need to excrete protons or alkali in order to maintain the blood pH at 7.41 despite what we eat and drink, and what our cells choose to let into or take up from the blood.
So, What are The Alkali Our Women Extract from Their Food?
Products Food Made When Alive
They are molecules the body cells can utilize as fuel and in the process oxidize mainly to carbon dioxide and water. But – watch out! – they are taken up into cells and oxidized with a proton, because they are actually acids.
Think about potassium citrate, a molecule well known on this site.
Citrate as An Example
Citric acid is a proton donor of considerable force. It is also critical to one of the most important metabolic energy producing cycles we own, called, incidentally, the citric acid cycle.
What we eat can have in it considerable citrate, the acid molecule that has given up its proton. Being highly charged negative (where the proton would bind) it must be accompanied by a positively charged atom or molecule – usually potassium, K, as shown here. Nature never allows highly charged molecules to swim in water unaccompanied by some opposite charged mates.
Note that citric acid has three negative sites to hold a proton, presently occupied by potassium atoms. So it can take up and give out three protons. When all three are in residence we call it citric acid; when even one is missing we call it citrate.
Plants, especially, have a lot of citrate, but even meats have it because the cells were once alive and processing this molecule. We absorb it with its potassium, or sodium, or calcium, or magnesium (all positively charged atoms). Some will be metabolized, but to enter into the citric acid cycle it must take up a proton, and the only place to get the proton from is the blood.
So citrate acts like a base in the body. The linked article reviews all of the forgoing material in a lot of detail.
Citrate is Just an Example
Citrate is part of an army of like molecules, perhaps hundreds of them.
Cells traffic in acids that are made into each other, transformed in the process of producing energy and things cells need to make. We eat the acids mostly without their protons, which have been left behind in the blood of the animal or sap of the plant before it was taken for us to eat, and for the most part – in animals at least, removed by the kidneys.
So, although I have used citrate as a familiar example, when you think about women taking up more alkali from food than men do, it is not citrate alone but a vast variety of molecules like citrate: Acids without their protons, that can take up protons in order to enter our cells and be useful to them as nutrients.
How Can We Measure The Alkali We Eat?
As Something Missing
Because alkali come in to our blood with their positive charged mates, sodium, potassium, calcium, and magnesium, they will show up in urine as a gap, a space between the sum of charges from these charged atoms and their main negative atomic counterparts, chloride and phosphate. They are there, the alkali, in the urine, but we detect them only by the charge gap.
In principle, with modern high speed systems, we can measure all of the anions in urine and determine each one by name. But for the present purposes that would add nothing of importance.
How Do We Do It?
We simply measure the concentrations of all six charged atoms, multiply each by its number of charges, and calculate the gap.
The concentrations are in moles, weights scaled to the sizes of the atoms.
The number of charges on an atom are known: sodium, potassium, chloride are 1; calcium and magnesium are 2. Phosphate is strange, because it has 2 protons that can stay on it or leave depending on the pH of the solution it is in. In blood, pH 7.4, its charge is 1.8.
We can call this quantity measured by a gap, by what is missing, absorbed food anion.
But the common term is GI anion.
Did Women Absorb More GI Anion?
Of course. Why else would I lead you through this labyrinth?
Fasting and overnight women and men look much alike. But look at the blue bars. Women tower over the men.
Remember, this was exactly where their urine was more alkaline – higher pH.
Also, remember what GI Anion is: Just the difference in net charge between the positive and negative atoms.
And, the men and women ate the very same food. Men eat more, of course, than women, being larger. But that will not much matter. We are measuring a difference of charges.
The difference in GI anion between women and men, fed, is 2.1 mEq/hr and our fed mean is over 12 hours meaning an additional flowthrough of 25.5 mEq over the fed period.
But, This is In Urine
This anion, measured like a ghost – as a space missing between two solid masses, is what never got used in the body, It came in as something cells could eat but did not, and left the way it came. So these ghostly molecules did not take up their protons and become food. They escaped altogether and were lost.
Why then did the urine pH rise?
Some Was Metabolized
How can we know that?
Well, if it were, we should seen signs. For example, urine might have more alkali. Blood, too.
Urine must have had more alkali. Its pH went up, meaning fewer hydronium ions.
But this is all indirect and conversational. Charming, perhaps, but not what one hopes for.
If I am to fully narrate what happened, I need to enlarge the circle of our mutual acquaintances.
We must understand the ways of another player, one possessing an overwhelming power and versatility in the kingdom of acids and bases.
We need to make familiar to us the prince of alkali, bicarbonate: Magister Ludi.
Bicarbonate and the Great Cycle
You can buy a five pound box of sodium bicarbonate on Amazon for $3.41. But it is a magical material.
What We Name Things
Carbonic acid readily gives up its proton, to become bicarbonate. But it also decomposes into CO2 gas dissolved in water, and dissolved gas rapidly enters and leaves water from the surrounding atmosphere. Bicarbonate itself has one proton it can donate to become carbonate (CO3—) if it has a base that accepts it.
So between its decomposition into CO2 gas, and its ready way with donating protons, carbonic acid will be only a very small fraction of total carbonate species – dissolved CO2 gas, carbonic acid, bicarbonate, and carbonate – in solution. Of the total, most will be bicarbonate.
We call the total of all four carbonate species ‘TCO2‘, and TCO2 is what we most commonly measure.
But bicarbonate itself has a special place, because it is the main donor and recipient of protons in water.
This nifty figure is from an equally nifty presentation of the true arithmetic for calculating things in this very complex molecular universe. It is complex because of what I have just said, that the bicarbonate system is equally at home in air – as CO2 gas, and in water – as dissolved CO2 gas and its spawn: carbonic acid, bicarbonate, and carbonate.
At the top is bicarbonate, as a proton acceptor next to its proton. It can slowly decompose into CO2 gas and water, and the dissolved CO2 gas can leave into thin air. Bicarbonate can be made very rapidly when carbonic acid (lower left) simply gives up its proton. Carbonic acid, like bicarbonate, can slowly decompose into CO2 and water.
But these reactions go both ways. CO2 and water can slowly make carbonic acid or bicarbonate. Thence the double arrows.
In the human body, CO2 is made by cells as they metabolize their nutrients to make energy for their work, and removed through the lungs. And that removal is regulated, so the dissolved CO2 gas is very constant.
If protons enter the blood, bicarbonate can take them up becoming carbonic acid – the fast reaction. Carbonic acid decomposes to dissolved CO2, and dissolved CO2 reacts with water to make carbonic acid or bicarbonate only slowly. So, a steady stream of protons can push down the concentration of bicarbonate, whereas a stream of alkali can raise that concentration – by pulling on carbonic acid and dissolved CO2 to make more bicarbonate. Remember, these are equilibria, the ratios of the players will maintain themselves.
Carbonate itself is not on the figure because it releases its proton only at pH values far above blood or urine, so it is a very minor component. Even so, TCO2 includes it.
You Need Not be a Body
Put water in a bottle. Get a tank of CO2 gas. Figure out a way to put a high pressure of CO2 gas into the bottle. Carbonic acid will be made, convert to bicarbonate, bicarbonate will give up protons making the water more acid. You have made carbonated water – acid tasting, bubbly.
Now, spoon in some proton acceptor – like phosphate. It will begin to soak up protons. If you keep the CO2 gas pressure high more carbonic acid will be made and give up its protons to make bicarbonate. You are making a form of Pepsi or Coke, but without the ingredients to make it taste nice. You are making bicarbonate out of thin air – CO2 gas.
Our fastidious and highly evolved cells tolerate changes in blood pH poorly, very poorly.
As protons come in or go out, bicarbonate takes them up or gives them out to keep pH constant. As it takes them up, bicarbonate becomes carbonic acid which vaporizes into dissolved CO2 which can leave the blood in our expired air. As it gives them out, carbonic acid becomes bicarbonate, and continuously restores itself from dissolved CO2 gas, which our cells are always manufacturing in their processes of metabolism.
So the bicarbonate system – if I may use this term – ‘buffers’ blood pH, keeps it relatively constant despite the comings and goings of protons. But buffering leaves a mark, or signal of its actions. As it takes up protons bicarbonate vanishes into carbonic acid and CO2; as carbonic acid gives protons out it becomes bicarbonate which appears in blood as if from thin air – which is in fact true.
Did Our Women Make More Bicarbonate?
If they actually used some of the GI anion, did not let it go into the urine but took it up into cells with a proton, that would be to make new bicarbonate. It is a removal of protons from blood, and the bicarbonate system must respond in the only way it can.
We can look in urine and ask if more is being lost, but that could mislead us. It might be lost from blood. We can look in blood, but that can mislead us – it might be retained by kidneys. We can look at both, and see what we can see.
Urine Total CO2
Urine total CO2 rose.
You knew it would. Could I have pestered you if it did not?
Think about this. The GI Anion we measure is anion what was absorbed from their food. It was lost in the urine. Lost from the body and lost as a source of new alkali for that body.
Instead of taking up a proton and serving as food for cells, it left, without ceremony, in the urine. Essentially it left as it came in, without effect.
But at the same time, with food, urine total TCO2 rose, a lot.
The sex difference in the amount of TCO2 excreted over the 12 hours of the fed period was 0.85 mmol/hr x 12 hours or 10.2 mmol in total. This is about 1/2 of the sex difference in GI anion I calculated just above as 25.5 mEq/12 hrs of the fed period.
That must mean women made new bicarbonate, or that the kidneys decided to lose bicarbonate from the blood into the urine.
How can we tell the one from the other?
That is not hard. We can measure TCO2 in blood.
Be clear. I have already said that almost all of the CO2 species in blood – and urine, too – is bicarbonate.
Serum Total CO2
It rose, too, at the same time.
It need not have to prove my case. If it just stayed constant and yet urine bicarbonate rose, it would have been proof enough that new bicarbonate was made. Only a fall in serum bicarbonate would have shredded my case.
In other words, women must have absorbed more GI anion than men, and converted some of it into bicarbonate, leaving the rest to go into urine.
Extracellular Fluid Bicarbonate
We measured TCO2 in serum, but this small molecule spreads out beyond blood into the much larger pool of fluids that bathe the body cells.
If we assume the total volume of fluid outside the cells (includes serum) is about 14 liters, and the total CO2 is dissolved throughout it – very approximate estimates indeed! – the difference between men and women amounts to 1.2 mmol/l x 14 or 16.8 mmol produced. If we add this to the difference in amounts in the urine, 16.8 + 10.2 we get 27 mmol of new bicarbonate difference.
This is about equal to the GI anion that was lost in urine and therefore not used to make new CO2.
We can estimate – very crudely and with reservations – that about 1/2 of the GI anion the women absorbed was converted to new bicarbonate, the other half was lost in the urine.
Blood Matters Most
Let’s be clear here. Traffic through from GI tract to bicarbonate or urine is interesting to physiologists. But the cells feel what is in the blood.
During their alkali adventure, women present to their cells a not inconsiderable alkaline bath. I lasts, in our case, about 10 hours as the bars average the three meal periods of a day. When I speak about this bath I mean the increase above fasting.
Men do not do this. Their serum TCO2 does not increase with food to any significant extent. Even if we ignore statistical significance and just look at absolute changes, men increased their blood total CO2 by 0.4 mmol/l whereas women increased by 1.7 mmol/l. The mean increases of 1.7 and 0.4 for women and men, respectively, applies to the entire fed period of about 12 hours. So one can say that food gives women an increased concentration x time benefit of (1.7 – 0.4) x 12 or 15.6 mmol hr.
The Value of Alkali
I have no way at present of quantifying what this might mean for the body cells, but contemporary science discloses some negative effects of acidity, so more alkali could have important benefits.
bone may suffer mineral loss from acid load especially with age. A recent review mentions less than ideal responses of multiple health outcomes to chronic low grade acid loading from our current diet. While we need a lot more study of the matter the regular alkaline bath to which women treat themselves daily may well improve their overall health in comparison to men.