The 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?
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?
Calculation and experimental determination of calcium binding by citrate is complex. Partly, all 3 oxygens can accept a proton, so the 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 calculated. Yet 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.
The 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 they 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
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.
69 Responses to “CALCIUM BINDING BY CITRATE”
Hello Dr. Coe,
Can oxalate crystals form and settle all over the body causing joint pain and stiffness? Since I have IBS-C I have trouble eating foods with calcium or taking supplements. My recent blood work revealed these results. Sweet potatoes help my inflammation tremendously but have severe joint pain and stiffness. Am I riddled with these crystals and will adding the calcium citrate and potassium citrate help bind the stones and, hoping the calcium does not prevent elimination problems, excrete them? I am also weary of adding potassium because when eating a banana after exercising, I had a weird nerve sensation all over my body at night that would not allow me sit still without extreme discomfort. This happens with onions, sweet peas, corn but not with sweet potatoes. My appt with my primary doctor is not until June but here are my red flags from my recent blood work. I am hoping with your expertise you can give me some direction to help me understand what is going on.
Globulin = 1.7 g/dL. ( Low)
Albumin/ Globumin ratio = 2.6 g/dL (high)
Vitamin D 25-OH=12 mg. (Low)
calcium 8.7. (Put total for information)
Thank you for your attention and any insight you can offer me is greatly appreciated.
Fredric L Coe, MD
Hi Leslie, Absent severe kidney failure, oxalate crystals do not exist in the human body apart from the interior of the renal collecting systems. I do note you have vitamin D deficiency and a low blood calcium, and treatment with Vitamin D might be something your physician might want to undertake. If you do not have kidney stones I know of no reason to use potassium citrate. Regards, Fred Coe
Thank you Dr. Coe.
Perhaps the low Vitamin D and Calcium is the reason for my joint pain, swelling and stiffness. I hope it is not my kidneys.
Fredric L Coe, MD
I would ask your physician if vitamin D might not be of value. Fred Coe
Thank you Dr. Coe.
I sincerely appreciate your insight.
As a Black Tea lover and Ideopathic Calcium Stone Former, I am looking for a way to incorporate my favorite beverage back into my diet. I have not passed a stone in 8 years after 15 stones in 12 years, the result of diet modification. Above all, I aim to not pass another.
This paper from 2002 (http://apjcn.nhri.org.tw/server/APJCN/11/4/298.pdf) analyses oxalate content of teas and also calculates (though doesn’t measure) the binding capacity of milk in tea (25% milk to 75% tea). Dr. Coe, I see you writing extensively on the effect of Potassium Citrate on urinary calcium output, and indirectly the concentration of urinary oxalate.
What about the use of Calcium Citrate dissolved in the steeping liquid for tea in order to bind with the oxalate before it can even be absorbed? My traditional two cups of milked tea with the addition of a typical supplement pill (Kirkland brand) of 500mg Calcium Citrate, one Cup water, one Cup milk, and about 4g of tea, would it not seem likely to bind a substantial amount of Oxalate? 4g of the highest Oxalate containing tea from the paper would contain 26.6 mg Oxalate (in line with the Harvard List’s 28mg for that amount of tea). Addition of this supplement had no affect on flavor.
Dr. Coe, any thoughts?
(joking) Anyone with an HPLC able to do a thorough study?
Fredric L Coe
Hi Eric, Milk with tea should work, calcium citrate might ruin the flavor. But the general idea is sound. Do it and get a new 24 hour urine to be sure oxalate has not increased. Regards, Fred Coe
Is there a difference between taking Calcium citrate and potassium citrate for kidney stones?
Frederic L Coe
Hi Sandra, there is indeed. Calcium citrate is important for bone, and also used as a calcium supplement against oxalate absorption. Potassium citrate is an alkali load to offset uric acid stones, or raise urine citrate. I assume you form kidney stones, but what you do for prevention depends on exactly what is wrong with you as a cause of stones. Consider this as a good introduction, and this as a more advanced version. Regards, Fred Coe
Dear Dr Coe,
Thank you so much for this informative and fascinating explanation of the role of citrate in inhibiting the formation of calcium stones.
I have an asymptomatic non-obstructing lower pole stone that is most likely a calcium oxalate stone, based on the analysis of a previous stone I passed. My current stone has been slowly growing for a number of years, and although I will no doubt eventually have to undergo a procedure to address this pesky little passenger, I’m very keen to delay that day — perhaps even for some years, considering the promising new treatment methods on the horizon (namely SonoMotion’s BreakWave and StoneClear focused ultrasound approaches, currently in development.)
To that end, I have not only significantly increased my daily water consumption, but have taken to drinking adding fresh lemon juice, having read several studies that suggest that the citrate in lemons may impede the formation of calcium oxalate stones. I understand it will have no effect on the existing stone. My goal is only to impede further growth.
After reading your article, I am greatly encouraged, as I had been wondering if consuming lemon juice was just wishful thinking on my part. Your clear explanation of the science behind the effect of citrate on calcium stone formation provides great motivation to continue my current course of action, with a follow up scan in 6-12 months to try to determine what degree of growth has occurred. I’m very hopeful that the stone will show little change.
Thanks again for taking the time to write such an illuminating article, and for sharing it here.
Fredric Coe, MD
Hi Shaun, Raising urine citrate to offset stone growth is a good idea unless your 24 hour urine citrate is already adequate. If it is, you might just raise the urine pH and promote overgrowth of calcium phosphate salts. Be sure about your 24 hour urine stone risks before undertaking presumed treatments, because otherwise things might get worse. As for lemons, I despise their use. A generall array of fruits and veggies – 5 servings a day – is recommended for all Americans and will provide as much or more alkaline anions along with finer nutrition. Regards, Fred Coe
Thanks for your reply. I will talk to my doctor about getting a 24 hour urine sample analysis before getting too carried away with home treatments to inhibit stone growth. To be honest, I won’t be sorry to give the lemons a miss, although the plus side is that after nearly a week of lemon juice just about every other fruit tastes amazing in comparison. Many thanks for your advice, and for the wealth of information you have provided on this site.
Dear Dr Coe. Is lemon juice effective in dissolving calcium oxalate stone ?
Fredric Coe, MD
Hi Abhijnan, No; nothing dissolves calcium oxalate. You need prevention. Take a look here for a plan. Regards, Fred Coe
Good morning Dr.
How can abuse of vitamin C increases calcium oxalate stones , and how can citrate cause low PH of urine?
Fredric Coe, MD
Hi Pierre, vitamin C can convert to oxalic acid. Citrate cannot lower urine pH – but citric acid can. Regards, Fred Coe
Dear Dr Coe,
What if you have a cat with chronic kidney disease and you feed a cat food with potassium citrate added. And you want to add a calcium carbonate binder to bind up phosphates in the food. Would calcium in the carbonate bind to the phosphates (what is wanted) or to the citrate, or both. This is a dilemma. Hoping you can advise me. And would using calcium acetate instead make a difference or would it be the same. What if you use AlOH instead. Thanks.
Fredric Coe, MD
Hi Jules, Veterinary medicine is a speciality I know nothing about, and I would be wrong to offer advice. Cats do form calcium oxalate stones, but their treatment requires a real expert. Regards, Fred Coe
Dear Dr Coe
On a slightly different matter – citrate in blood – I do platelet apheresis and I expect you’ll know that citrate is used as an anticoagulant in this. Some is returned to the donor. Where I do this (in the UK) there’s concern about the citrate complexing blood Ca++ and so causing cardiac arrest. I usually get about 330 ml of 3% sodium citrate per session, and have none of the classical finger tingling or anything. I drink about two pints of milk in the 6 hours beforehand to keep up my Ca level. None of the nurses in charge can tell me how much Ca I should ingest; I calculated this amount of milk on the (incorrect) basis of one mol Ca reacting with one mol citrate. I’d be interested to know what your views on the use of this angicoagulant in apheresis. I think it’s safe as I survived 80 sessions with no effects. Many thanks, Vic Breeze
Fredric Coe, MD
Hi Vic, Citrate is well known as a systemic anticoagulant, and your physicians are doing nothing I could criticise. Regards, Fred Coe
Anthony J Perrotta
Dear Dr. Coe,
The chelating of the divalent calcium ion by citrate anion to keep the calcium ion in solution rather than combining with oxalate or phosphate anions to form stones. Basically, as I understand it, this chelating effect prevents supersaturation of the combining of oxalate or phosphate with calcium to form stones.
What fruit juice would you recommend to supply the citrate anion to give the required chelating effect?
Anthony Perrotta (PhD Chicago, 1965)
Fredric Coe, MD
Hi Anthony, indeed citrate complexes with urine calcium to form a very soluble salt. That reduces free calcium molarity. Oxygens on citrate also bind to surface calcium ions in calcium oxalate and calcium phosphate crystal nuclei competing against oxygens from phosphate and oxalate. This tends to disrupt orderly crystal growth and can provoke dissolution by disordering the surface charge array. Urine citrate is determined by the NaDC1 transporter that responds to pH of the proximal tubule fluid, so any alkali will raise urine citrate. Fruit juices are a miserable way to provide metabolizable anions because they collect the fructose from many fruits into a concentrate. Fructose – all sugars – raise urine calcium and fructose is a genuine health hazard. The best is some form of potassium citrate or else a diverse array of fruits – not the juices – and veggies that all contain abundant Krebs cycle precursors. Best, Fred (MD Chicago, 1961)
Hi Fred, I have calcific rotator cuff tendonitis. Does taking Potassium Citrate help break down calcifications in the shoulder at all? Apparently, I’m excreting electrolytes in my urine. My doctor first said it was because I was taking D-mannose, but I haven’t been taking D-mannose for months and my urine electrolytes are still high. My doctor doesn’t have an answer as to why. Do some people excrete more potassium in their urine than others, and if so, why is that? Could excreting more potassium causes the body to be more prone to forming calcifications? Thank you, Susan
Fredric Coe, MD
Hi Susan, No; it will not help calcified rotator cuff disease. Taking citrate will not influence blood citrate. Anything that lowered serum calcium ion so joint crystals dissolved would endanger life – the brain, heart, etc all require serum calcium levels be very constant. As to urine potassium it faithfully follows diet and drug potassium intake – it is an atom. Likewise for sodium. So, you must eat more potassium than is usual – fruits and veggies are the usual source. But be happy; on average our urine potassium runs 40 – 60 mEq/day. The US ideal is over 100 mEq/day. Potassium intake has not effect on joint calcium content. Regards, Fred Coe