MeThe citrate molecule in urine is thought to protect against formation of calcium stones. This thought began as reasoning from chemistry, and culminated in clinical trials which substantiate the idea. As a result manufacturers produce citrate products for medicinal use, and doctors prescribe the medicine.

All this is a wonderful success story, a kind of perfection of the paradigm of translational science: From science to a treatment for patients that reduces illness from kidney stone disease.

But what, exactly, is the science? Can scientists not enjoy the story of such a success, physicians derive from it a deeper understanding of the drug they so regularly dispense and patients the comfort that a perfected knowledge support the rightness of their prescribed treatment?


The Molecule

As usual in such diagrams the carbon atoms are simply angles or kinks. Reading from left to right, there is a carbon atom bound (the solid lines) to two oxygen atoms (‘O’), one with a single and the other with a double bond. These bonds represent sharing of electrons by the atoms.
The single bonded oxygen has an extra electron in its outer shell, so it carries a negative charge (-). Calcium is an atom with two positive charges, so the idea of calcium and citrate binding to each other comes naturally as one thinks about opposites attracting one another.

Next in line is another carbon atom; the kink means the carbon is linked to the carbons on its left and right and to two hydrogen atoms. The hydrogen atoms are necessary because every carbon atom makes four bonds.

After that, is the third carbon which is very occupied. It has an oxygen which is itself bound to a hydrogen – a hydroxyl molecule, really 2/3 of a water molecule – and another carbon bound to two oxygens, one of which has a negative charge. To the right of this busy carbon the molecule repeats itself as in a mirror.

How beautiful nature is, how powerful its symmetries and suggestive its forms!

It is as though some great sculptress were taken with an image of perfection that a string of carbons might take the perfect form to mate with calcium, tiny in comparison, and doubly charged positive.

But how? How would the mating occur? If you do not look down, could you have imagined it?

Binding Constants

Calculation and experimental determination of calcium binding by citrate is complex. Partly, all 3 oxygens can accept a proton, so CALCIUM ION VS CITRATE MOLARITYthe acidity of the solution – urine in our case – matters. Partly, binding is complex. As shown in the section below, it involves forming a ring structure and a bi-molecular structure. In general calculations are performed using computer programs.

But simple experiments give a reasonable gauge of the power of citrate to bind calcium. In the figure adapted from Table 2 of the reference at the top of this section, when the molarity of calcium and citrate are equal, at both 2.5 and 5 mmol/l of total calcium (2.5 – grey circles and 5 – black circles in the legend), a common range in urine, only about 1 mmol of calcium is unbound and therefore a free ion that can combine with oxalate or phosphate to make a stone. From the shapes of the graphs, citrate is a powerful binder as the calcium ion falls almost linearly with citrate molarity.

This graph is very approximate. Actual calculations of citrate binding effects have to consider pH, ionic strength, and many varieties of citrate calcium salts. These are part of how supersaturations are calculatedYet for all its simplifications, this graph of ancient data suffices to show what citrate can do as a protection against urine crystallizations of calcium salts like calcium oxalate and calcium phosphate. 

Calcium Citrate Crystal

But this is not a complete story. What if calcium and citrate combine to make a crystal which becomes yet another kind of stone? They can indeed form a crystal, but one which is so soluble it is never a stone risk. Even so, how the crystal forms is a way to show how the molecule binds calcium, which is in itself simply very interesting.

Creation of the Di-Citrate

I have made this structure the featured illustration for the article, but put a copy here for visual convenience. Would you have imagined the two ends of the molecule would bend around to hold the calcium, which makes what was linear into what is, now, a ring?

Just below is another ring, identical in character. Neither is a crystal, merely they are a pair of rings.

But, that odd outcropping of a carbon atom on the original molecule has its charged oxygen, and through another calcium, caught there, the two are linked.

Citrate has two ways to bind calcium. A single molecule can bind one calcium atom. Two citrate molecules together can bind one calcium atom. So the ratio is 1.5 calcium atoms per molecule of citrate (3 atoms/2 citrate molecules).

The Making of a Crystal

How these paired rings make a crystal is not an easy story to tell. Here is a good reference which I will explicate not as a crystallographer, which I am certainly not, but as a narrator telling a good story.

calcium citrate crystal jpeg versioinThe calcium citrate crystal is built up out of repeating units, each of which is a pair of citrate molecules linked by a calcium atom. This ‘di-citrate’ unit has three calcium atoms in it, one in the center, which is unique, and one at each end which mirror each other. These are in the diagram just above.

All three coordinate with 8 oxygen atoms. By this I mean that in addition to the 2 oxygens shown in the simple figure of the di-citrate molecule, oxygens are shared that belong to di-citrate molecules ‘above; and ‘below’  and to the sides so as to make a set of plates like the floors of a parking building.

This complex macrame shows all three calcium atoms. The middle one – calcium 1, at the center of this drawing – relates to 6 oxygens bound to carbon atoms, and to two belonging to water molecules that are pulled into the final structure. The second – at the left lower corner – is coordinated by 8 oxygens bound to carbons, and the third – at the right lower corner, is coordinated with 7 oxygens bound to carbon and one hydroxyl (OH) bound to a carbon (see the simple di-citrate drawing).

This crystal, calcium citrate, is actually a medicinal product (‘Citracal’™) which when swallowed in a pill form dissolves in the gastrointestinal tract to donate calcium and citrate that can be absorbed into the blood. The crystal itself is not found in urine. The medication is of no immediate interest concerning stone disease because one does not use it as a treatment for stones but rather as a supplement for bones. Whether or not it might be helpful in preventing stones would require a trial.

The citrate used for stones is potassium citrate, which is simply the single citrate molecule with its 3 negative charges satisfied by potassium ions or protons.

Why, then, have I troubled you with the elaborate business of citrate calcium binding and crystal formation?

Because it is one way that citrate protects against stones. The molecule binds calcium which is therefore no longer free to combine with oxalate or phosphate to form kidney stones. The crystal calcium and citrate forms does not make stones because it is very soluble. If it were not, citrate would not be a protection against stones but merely the substrate for yet another calcium type stone.

Solubility of Calcium Citrate

What, then, is the evidence for this statement – that the calcium citrate crystal is so soluble that it does not make stones? I have said it several times but have provided you with no proof.

The three oxygens of citrate are partially occupied by protons, and when calcium citrate solubulutythey are they are not available to coordinate with calcium to make the di-citrate and its crystal. Therefore the solubility of citrate will be influenced by the concentration of protons, the acidity of the urine, represented here by pH.

The experiment is done by adding crystals to a simple salt solution, letting them equilibrate with the solution at a constant temperature, and measuring, in this case, the concentration of calcium that is in the solution, having left the crystals as they dissolve.

Two of the three oxygens are ‘weak’ acids which are half saturated with protons at pH values of about 3 and 4, meaning that throughout the range of urine acidity – pH 4.5 to 8 – both are free to bind with calcium. The third is at pH 6.4. One might expect an increase in calcium binding as pH rises above this point, but there is no obvious change in the solubility of the crystal between 5 and above 7.

At pH of 6, the mean for normal urine, the concentration of calcium in solution is about 0.2 mg/ml or 200 mg/liter. Given the atomic weight of calcium – 40- this is 5 mmol/liter. Calcium oxalate crystals dissolved in the same way yield a calcium concentration below 0.005 mg/ml or 5 mg/liter which is about 0.05 mmol/liter. Calcium phosphate crystals give a value of 0.08 mg calcium/ml. 80 mg/liter or 2 mmol/l, less than half of the citrate.

Since calcium and citrate are released from the crystal in proportions of 1.5 calcium per di-citrate, one presumes the equilibrium citrate molarity will be 66% of calcium or 3.3 mmol. Given the molecular weight of citrate is 192 mg/mmol, this amounts to 633 mg/liter of citrate. That is a high concentration of citrate, given that common excretion rates are rarely above 750 mg/day and urine volumes about 1.5 liters a day. Even so, some urine samples almost certainly achieve these concentrations of calcium and citrate on occasion. But equilibrium is not enough to create new crystals; one needs to achieve a higher value so that new crystal nuclei will form. That will be very unlikely for calcium citrate.

So citrate can combine with calcium to remove it from binding with oxalate and phosphate, and form a crystal of considerable solubility. Being very soluble, calcium citrate is rarely if ever found as a kidney stone.

Calcium and Citrate in Urine

calcium - citrate picture

One of two crucial issues about citrate in stone prevention is the relationship between the concentration of calcium and that of citrate. The higher the concentration of citrate compared to calcium, the lower the concentration of unbound calcium, which is free to combine with oxalate or phosphate to make kidney stones.

This graph from our research work shows the difference between urine calcium and urine citrate concentrations for normal people (red), and calcium phosphate (blue) and calcium oxalate (yellow) stone formers over the full day and overnight periods. These two kinds of stones have already been reviewed on this site. 

Normal people have lower urine calcium excretion rates than stone forming patients, but about the same excretion rates for citrate, so the calcium – citrate difference is below 1 mmol/liter. In the graph above which shows free calcium ion at two concentrations of total calcium – 2.5 and 5 mmol/l vs. citrate concentration, when the calcium and citrate concentrations are equal the free calcium is below 2 mmol/liter. When citrate concentration exceeds that of calcium, the free calcium will be lower.

Both of the patient groups have much higher calcium excretions than normal people and because their urine citrate excretions are no higher, and perhaps even lower than among normals, the concentrations of free calcium are much higher, in the range of 2 – 3 mmol/liter.

It is this kind of information which has long made scientists believe that citrate is an important factor in the normal defense against calcium stone formation, and which led to the successful trials which proved that this believe is not unfounded.

What is the Real Science?

The citrate story illustrates all the three forms of scientific research.

Empirical science is what we would call the meticulous measurement of the binding constants between citrate and calcium, and the specific structure of the calcium citrate crystal. It is also what we would call the pretty graph of urine calcium – citrate differences in normal people and stone forming patients.

Applied science is the trials which showed that the intuition of citrate as a treatment was a true intuition. It is indeed a treatment, and that is a fact which time will not alter.

Basic science, however, is not so obvious here. Where in the story do we encounter the passion or curiosity to ask how citrate has come to be in urine.

Certainly citric acid plays a role in biology vastly  – one might say infinitely – greater than that of stone prevention. It is the key molecule in the citric acid cycle which is so well known that I have only to reference it from Wikipedia. Known to schoolboys and schoolgirls everywhere, this cycle is used by all aerobic organisms to generate energy, and is of an extreme ancient origin.

Surely a molecule of such lineage and power is ruled little if at all by the problems of renal crystals. Yet it is handled by the kidneys with considerable finesse as if somehow important to the renal system or – perhaps – as if the renal systems were somehow important in the larger matters of maintaining serum levels of the molecule.

Here is imaginative science. Here is the place where a question of underlying cause comes into focus. Here is where nature presents issues of monumental consequence.






  1. Gus L

    Hi Doc
    I am wondering Can you use calcium citrate in combination with potassium Citrate for the treatment of Calcium oxalate bladder stones?

    • Fredric Coe, MD

      Hi Gus, A lot depends on the stone. If it is uric acid, potassium citrate is ideal. If calcium based, it depends on whether it is oxalate or phosphate. Most important, bladder stones often arise from incomplete drainage and benefit from urological intervention. I do not use calcium citrate for stone prevention, in general. Regards, Fred Coe

  2. Silvia

    Hi Dr. Coe,
    I heard that one should avoid calcium carbonate and go for the citrate instead in order to avoid the formation of kidney stones. Is it true? Also are magnesium and potassium citrate ok? Thank you

    • Fredric L Coe, MD

      Hi Silvia, I am not sure of what one is treating with either one. Calcium citrate is given as a means of supplemental calcium, and is fine. Calcium carbonate is usually an antacid. Potassium citrate is to increase urine pH. And magnesium citrate would cause some GI disturbances. If you can tell me what it is you want to accomplish I would try to help. Regards, Fred Coe

  3. Chris M

    Thank you for this in depth information! I’m trying to determine if the addition of calcium citrate to chocolate would cause it to bind the oxalic acid present in the cocoa solids once they have been consumed together and are in the digestive tract. I am trying to blunt the potential impact of the oxalic acid from the cocoa solids when they are consumed and calcium citrate seems promising, but I don’t fully understand the mechanistic side. Thank you, Dr Fred!

    • Fredric L Coe, MD

      Hi Chris, I guess in the abstract calcium will bind oxalate in chocolate, but practically that might end up a mess. If you drink some milk along with your chocolate, I would guess urine oxalate will rise less, but no one has done that experiment – that I know of. Best, Fred

    • Stephen

      Hey Chris, did you have any luck binding the oxalates in cacao with calcium citrate?

  4. Judy Good

    I am curious. I already soak my gf grains (teff, sorghum, oat etc) for 18- 24 hours – in a solution of water with 60% lactic acid powder that has 700mg of calcium lactate in it already – the acidity is around to 4 – 5 pH at a temperature of 95-100F. I do this to reduce the phytate and other anti nutrients in the grains that interfere with digestion. My question is: during the long soaking period, would the oxalate in these grains bind to the calcium lactate – or do you think it could be beneficial for me to add calcium citrate to bind the oxalate? I know this is a different approach that the binding in the human body you present. But since I soak the grains anyway, I am wondering if I could reduce the oxalate in this manner? Thank you for your reply.

    • Fredric L Coe, MD

      Hi Judy, that pH with a lot of calcium might leach oxalate out of the food onto the calcium. But the lower the pH the less one will remove because oxalic acid has a pKa of about 3.5 and as one approaches that pH oxalic acid no longer can bind calcium. So pH 5 is a better bet. Please recognize this is mere inference as I have no data on this subject. Regards, Fred Coe

      • Judy Good

        Thank you for your reply. You offered helpful insight – even though this is an approach NOT presented here by your research…nor have I seen it anywhere….but theoretically, I am thinking might work to REDUCE oxalate levels in grains/flours (by binding some of the oxalate to the calcium – outside the body), and I am soaking grains/flours anyway. There is a typo in my question – in that there is 70mg of calcium lactate (NOT 700mg) in the lactic acid powder…however, I could easily add a crushed calcium citrate capsule to the solution. I will test to check and keep the solution to a Ph of 5…instead of the lower 4.3 Ph. and give it a try and see how it goes. Thank you again – for your insight….and for your article on this topic – it is very informative and interesting, regardless if my approach works or not.

        • Fredric L Coe, MD

          Hi Judy, You might want to measure your 24 hour urine oxalate to be sure things are doing well. Best, Fred

  5. Laura Bousada

    Dear Dr. Fred Coe,
    Will citrate work to discourage calcium phosphate stones? If so is there a particular one. I am only half way through your extensive writings on citrate but my question is burning so I need to ask now!! I do drink a lemon a day and wonder if this would help as a citrate substitute. At the beginning my nephrologist did have me on citrate. I could not tolerate it well, then found out I have phosphate stones.

    • Fredric L Coe, MD

      Hi Laura, I remember you well from when I was active on Facebook. Here is my best and latest on calcium phosphate stones. Treatment is a bit fussy and any alkali – potassium citrate or lemons – might worsen matters. Take a look, and see if it does not help clarify things. SO many MSK patients in your group seem to be more like calcium phosphate stone formers, I hope they are being recognized as such and treated effectively. Warm regards, Fred

  6. Fred

    Hello Dr. Coe. As someone who has to be really careful around oxalate I was wondering if the blood pressure medication I was given, amlodipine, would interfere with the calcium and oxalate binding that happens in the gut. I was reading about it and found out the medication is a calcium channel blocker, and being a layperson I’m not sure what that means. Appreciate the help.

    • Fredric L Coe, MD

      Hi Fred, No; the calcium channel is in smooth muscle and will not affect GI calcium absorption. Regards, Fred

  7. Miguel

    Hello, Dr. Coe, I have a question. Since calcium ingestion is recommend in order to bind with oxalate in the stomach and intestines so it can be excreted and not absorbed. Wouldn’t citrate “steal” all the calcium so that calcium wouldn’t bind with oxalate and this it would be absorbed more?

    • Fredric L Coe, MD

      Hi Miguel, Citrate is absorbed by the intestines and metabolized to bicarbonate. I guess if you took it with meals it might bind some food calcium, but usually one takes it separately. No data on citrate /oxalate competition in the GI tract. Great thought. Fred

      • Miguel

        Thank you for your answer, Dr. Coe. But I still have one question. Where does citrate interact with calcium to bind with it? I assume it’s not in the GI tract, given your explanation, because it is taken separately, so maybe it’s after they are absorbed, right? But if after absorption, citrate is metabolized to bicarbonate, where would citrate bind with calcium exactly?

        • Fredric L Coe, MD

          Hi Miguel, In the urine. Citrate in urine binds calcium so calcium cannot bind with phosphate or oxalate to produce stones. In the GI tract, let us say we have 800 mg of calcium in the diet = 20 mmol or 40 mEq. I suppose if you took 20 mEq of potassium citrate with a meal, and the meal were 1/3 or so of that calcium – 12 – 14 mEq – it might affect absorption. No data I know of. Regards, Fred


    Hello Dr. Coe,
    What would be the best salt of calcium to consume with a meal to bind oxalate in the intestine? (I already take potassium citrate for other reasons, so the idea that calcium citrate kills 2 birds is not a consideration). What would be the minimum amount of the preferred calcium salt per mg of oxalate consumed to create “100%” binding?
    Thank you

    • Fredric L Coe, MD

      Hi Burt, It does not work that way – I use calcium to lower urine oxalate in the context of a complete approach to stone prevention and that depends on the circumstances. Here is a good review of the common situation. You do not give enough information for me to be more specific. Regards, Fred Coe


    Hi Dr. Coe,
    I have flags on my urine test which I provided 3300 ml/24 hrs (since kidney stone surgery last month, i have consistently drank 90 oz of water daily for the last six weeks). I was taking a Vitamin D supplement once per month in the amount of Vitamin D2 50,000 1.25 mg for deficiency for the last 18 months. I was also eating an extremely high oxalate diet and not eating any calcium except for what spinach and almond milk and almond flour was providing. My urine test showed i have a low creatine level at 712.8 mg, low cystine at 4.69 mg, very high oxalate level at 73 mg, and my calcium was 112.2 mg and citrate was 98 mg. I have started to increase diet calcium, lower sodium (my level was of sodium was 99 mmol/24 hour urine) and majorly decrease the oxalates. Do you think I should take calcium citrate as well? Thank you so much for all of your comments and articles on this site!

    • Fredric L Coe, MD

      Hi Nicole, I believe I have answered these questions in my prior two responses. The high vitamin D intake possibly has raised your urine calcium, but I think it likelier that you have idiopathic hypercalciuria as already noted. Regards, Fred Coe

  10. Micah Brown

    Hi Dr.Coe-
    I am trying to understand the relationship between calcium, oxalate, and the use of proton pump inhibitors. PPIs decrease create a more basic gastric environment (and according to this medical school lecture) this leads to more calcium bound to oxalate → reduced calcium reabsorption → increased risk of fractures in the elderly. Can you please explain the mechanism behind why the lac of acid will favor calcium bring bound to oxalate?

    Thank you so much and cant wait to read any insight you can give regarding this topic.

    • Fredric L Coe, MD

      Hi Micah, The theory you mention, a less acid stomach interior would reduce separation of calcium from phosphate, as well as from oxalate, so it can be absorbed. I think there is more to it. Because the pH inside the stomach is normally so low – about 1-2, it can protonate oxalate disrupting its binding to calcium. But I have not personally studied this area and want to limit my remarks here and instead do an article on the subject that will be proper. Thanks for asking, it is provocative and worthwhile. Fred


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