MeUp to this point we have considered only increase of urine volume as a means of stone prevention. The effect of increased urine volume is to reduce urine supersaturation with respect to stone forming salts and therefore reduce the risk of crystal formation which is the basis for kidney stones.



Supersaturation with respect to the calcium stones depends upon urine concentrations of calcium, oxalate, phosphate, and citrate, and, in the case of calcium phosphate stones, or uric acid stones, urine pH. Giving citrate salts can reduce urine calcium excretion and increase urine citrate. Urine citrate binds urine calcium in a soluble citrate complex, which reduced calcium salt supersaturations. Citrate inhibits crystal formation, growth and aggregation. The alkaline citrate salts can raise urine pH.

relative risk vs urine citrate from Curhan control file in stone bookEpidemiology

In a prospective study of two nurse (red) and one male physician cohort (blue) Curhan found that relative risk of kidney stone onset (vertical axis) rose as urine citrate excretion (shown in hexiles along the horizontal axis) fell. Below 400 mg/day of urine citrate risk was – compared to above 800 mg/day) increased by nearly 2 fold. Mean relative risk is at the ends of the shaded bars. The upper 95% of risk is at the tops of the filled bars. Even though the average risk (end of crosshatched bars) remained below 1.



Although I had quibbles with some of the comments it included, I believe the recent American College of Physicians (ACP) review of kidney stone prevention trials was done properly, and therefore have selected for review here those they felt were technically adequate.

Below is a detailed presentation of the five studies. Here is a link to my spreadsheet with all of the numbers. It also contains my references for thiazide treatment.

Ettinger et al (J Urol 158:2069-2073, 1997).

Sixty four patients with at least 2 stones in the past 5 years and at least 1 within the past year before the trial were given placebo (33 cases) or potassium magnesium citrate (63 mEq citrate, 42 mEq as potassium and 21 mEq as the magnesium salt in combination pills) – 31 cases. Each pill contained 21 mEq of citrate; 2 pills were taken 3 times a day. The trial was designed to last for 3 years. There were 5 and 9 women in the placebo and treatment arms. Urine citrate excretions were not different before treatment (549 and 587 mg/day, respectively, nor were urine volume, pH, calcium, oxalate, or any other stone forming risk. After a one month grace period in which new stones were not counted, any passage or radiographic appearance of new stones, or growth of previous stones was considered a treatment failure. During the trial, 15 subjects left the treatment arm, 8 the placebo arm.

New stones or growth of old stones occurred in 63.6% (16 cases) of the 25 placebo cases who finished the trial and in 12.9% (2 cases) of the 16 treated cases who finished the trial. If the 6 subjects who left the treatment arm because of drug adverse effects are added in as treatment failures the drug effect remained significant (8 of 22 or 33%).

Of note, this particular formulation is not available in the US. A version of the supplement is available OTC but the dose per pill is so low that it is impractical for anyone to use it. So the trial is part of a proof of principle, but not actually applicable to clinical practice in this country.

Lojanapiwat et al (International Braz J Urol 37:611-616, 2011)

Unlike the Ettinger study, which concerned spontaneous stone formation, this study concerned new stones or growth of residual fragments after shock wave lithotripsy (SWL) or percutaneous nephrolithotomy (PERC). Their subjects were 80 initial patients, all 8 weeks after either procedure, and either stone free or having no residual stone fragments >4mm diameter (Numbers are in the Table). Hypocitraturia (<325 mg/day) was present in 20/39 who received citrate and 15/37 who did not.

  SWL PERC  Total
STONE FREE 24(8)  15(5)  39(13)
RESIDUAL STONES 26(17)  11(9) 37(26)
Total 50(25)  26(14)  76(39)

They were randomized into 39 treated and 37 placebo treated groups and followed for one year which 76 of the original 80 completed. Numbers receiving citrate in each group are in parentheses. Sodium potassium citrate was given as 81 mEq/day in 3 divided doses).

Of the 13 cases who were stone free and received citrate, 12 remained so vs. 15 of the 26 given placebo. Of the 26 who had retained fragments and were given citrate, 8 were stone free vs. 1 of the 11 controls and 16 others given citrate showed no change (13) or reduction in size (3) vs. 2, no change and 2 decreased size among the 11 placebo. These differences were judged significant at the p<0.05 level by the authors.

Soygur et al (J Endourology 16:149, 2002)

This trial considered 90 patients after SWL for lower pole stones who had residual stones <5 mm or were stone free. They were randomly assigned to potassium citrate (50 mEq/day in 3 divided doses) or placebo (Table). The trial lasted one year. The end

  Citrate  Placebo  Total
STONE FREE 28(0)  28(8)  56(8)
RESIDUAL STONES 18(0)  16(6) 34(6)
Total  46(0)   44(14)   90(14)

points were stone free or not and residual stone size increased or not.

New stones occurred (parentheses) in none of the citrate treated stone free patients and in 8 of the placebo treated patients. Among the residual stone group, the fragments disappeared in 8 treated cases and failed to grow or shrank in the others vs. growth or new stones in 6/16 placebo cases. The differences in growth or new appearance were all significant.

Of course, both of these post treatment trials are subject to the biases of a radiography study, but observers appeared to have been suitably blinded to the patient groups.

Hofbauer et al (British J Urol 73:362-365, 1994)

In this trial, an equimolal sodium / potassium citrate was given in doses that maintained urine pH in the range of 7 to 7.2 vs. placebo. Therefore, although patients were allocated randomly to active treatment or placebo, the trial could not be blinded. By the three year endpoint, 22/25 placebo and 16/25 active drug subjects remained. New stones occurred in 16/22 placebo and 10/16 active drug subjects. This difference was not significant. This study is the only one with a negative outcome. It is also the only study that was not double blinded.

Barcello et al (J Urol 150:1761, 1993)

Stone formers with urine citrate excretion rates below 643 mg/day (3.4 mmol/day) were allocated to potassium citrate 60 mEq/day in 3 divided doses. Their mean urine citrate excretion was 359 mg/day. At the end of three years of followup, 20/28 placebo treated and 18/27 citrate treated subjects remained. New stones occurred in 14/20 placebo and 5/18 treated cases, a significant departure from chance.


TREATED  20  115 135 
NOT TREATED 77 71  148
TOTAL  97  186 283 

Despite the variability of design, one can, with nerve, simply ask about the beneficial effects of citrate salts across all the trials. In all five trials 283 people completed the desired treatment period. Of these, 97/283 (34%) formed new stones or, in the case of the post procedure trials showed growth of retained fragments. Among all patients who were given citrate salts, 20/135 (14.8%) formed new stones or showed growth of retained fragments vs. 77/148 (52%) of those given placebo.

I have not added back the 6 cases from the Ettinger trial who left because of drug side effects.

From this we can reconstruct a sense of the value of the treatment as applied to the mixed practice of post surgical management and overall medical prevention.

Let us assume these numbers will hold for the future.

For every 1000 cases like the ones in the trials, 520 untreated cases will form new stones or show stone growth after a procedure vs. 148 cases/1000 cases with citrate, a savings of 372/1000 cases overall.

I realize I am not calculating in the most satisfactory manner as a statistician, but I rather like the coarse grained, even vulgar nature of my count me up.


A Personal View

The trial community exhibits the kind of methodological fussiness one expects and applauds in any scientific situation. Among their ilk the citrate effect is viewed as modest at best, the evidence, by their likes, fair.

I am sure they are right according to the mores and social instincts of this discipline, but I do not come from nor inhabit that discipline, and therefore have an altogether different way of counting – for that is all one does after the impatient and often indifferent subjects have played out their roles in the work.

How likely is it, I ask myself, that citrate salts do not prevent new stones or fragment growth?

Not at all likely.

Why assume anything but that blinding was performed when specified, that radiograph readers were competent and blinded to the groups patients were in, that stone events were counted fairly and compared to radiographs to estimate new stones? If we make these assumption of honesty and skill, the marked downward skew from alkali is just too large to be by chance.

My bet will be on the drug, and if I bet that way, I will always win.

Do We Need More Trials For Calcium Stone Formers?

For me, no. It would seem a waste of money.

Some trials treated patients with reduced urine citrate, others did not. Some trials looked at new stones over 3 years, others at residual fragment growth one year after urological procedures. Will another 50 or even 100 cases be likely to change the outcomes? If so, in what way, and why?

It is true that one trial showed no effect and that trial was not blinded. It is actually a drag on the results as I did not remove it.

We Do Need a Trial of Citrate for Calcium Phosphate Stone Formers?

I do not know how often this must be said. Calcium phosphate stone formers must lurk in each of the trials I have reviewed, but I do not know their outcomes. One trial insisted stones be at least >50% calcium oxalate. That means perhaps a few had considerable phosphate is stones.

Calcium phosphate crystal formation is sensitive to urine pH whereas calcium oxalate stone formation will not be. The reason is that calcium phosphate supersaturation requires divalent phosphate be present, and the pKa for the second proton is about 6.8. Citrate salts can raise urine pH, so they can raise supersaturation with respect to calcium phosphate salts. On the other hand, citrate is an inhibitor of crystallization both because it is calcium binding and because it directly affects calcium crystal growth.


The very same ACP report from which I derived the studies shown here presented an annoying set of comments that infers we might as well just give a drug like potassium citrate without knowing stone composition, or doing serum or urine testing that concerns stone pathogenesis.

For this reason, I offer some remarks on that subject. This is in the special context of citrate treatment. I have made more general remarks of a negative sort about the APC comments.

Does Stone Analysis Matter?

How can it not? I have already mentioned the problem of phosphate stones. Do we not have to exclude struvite is stones? The odd patient with cystinuria who has slipped by? Drug stones? Conversion from calcium oxalate to calcium phosphate stones?

Do Serum and Urine Testing Matter?

How can they not?


Do we want to give potassium loads to people with reduced renal function?

Having prescribed potassium, do we not want to monitor for serious increase in serum potassium; some patients are older, some diabetic, some take ACE or ARB medications, some age or change drugs over the years we treat them.

Do we not want to diagnose primary hyperparathyroidism? You cannot without serum testing and 24 hour urine testing to be sure calcium excretion is not low.


If we do not obtain and measure 24 hour urine samples, how can we know anything? Some patients may have very high urine citrate levels. Some may have very high urine pH values.

Here and there urine oxalate is very high, from primary hyperoxaluria, or occult malabsorption syndromes, or very odd food habits.

People change their habits and develop diseases.

Moreover, people do not always take their citrate. Fall in urine ammonia in relation to urine sulfate, and rise in urine potassium assure one they are taking the drug.


Do We Need a Trial for Uric Acid Stone Formers?


No one really questions that alkali salts will raise urine pH, nor that raising urine pH will reduce uric acid supersaturation and prevent stones. It is common practice. I doubt anyone will pay for or perform an RCT to test this question.

That they will not is very important, because it raises an unexpected question.


We Know the Chemistry

Uric acid is a large flat mainly hydrophobic molecule with most of its charge on a single proton receptor site. The protonated from has a very low solubility in urine of around 90 mg/liter whereas 24 hour urine uric acid excretion ranges from 400 to over 1000 mg daily depending upon diet purine loads. The pKa of the proton receptor site is about 5.3 in urine. 

Given these facts we can calculate uric acid supersaturation from the urine concentration of total uric acid and the pH, along with minor adjustments for the effects of ionic strength on the pKa. High supersaturation will lead to a snowstorm of uric acid crystals. Raising urine pH to above 6 will generally reduce supersaturation below 1 and end uric acid stone formation.

Everyone Knows Alkali Work

There is a lot of uric acid excreted every day, so uric acid stones can grow rapidly. Uric acid gravel has an orange red color and is often seen. When alkali are given, the gravel goes away only to come back if patients miss doses. The absence of new stones is obvious.

No One Treats Without Stone Analyses

Who can be sure of stone composition without stone analysis? Even during treatment of someone who has produced uric acid stones, calcium oxalate or calcium phosphate stones may begin. So people know the stone type, and proceed by custom.

No One Treats Without Testing Serum and Urine

Uric acid stones are common in diabetics and people with reduced renal function; potassium loads are potentially dangerous. Perhaps this is more obvious among uric acid stone formers than calcium stone formers, although given wide spread use of ACE and ARB drugs and NSAIDS, potential risk is everywhere.

The amounts of alkali needed can be variable, and the only reliable way to ascertain is 24 hour urine testing. Likewise for compliance.

Therefore routine practice monitors before and during potassium citrate treatment of uric acid stones.


IN this situation, no one has and probably no one will propose a trial of alkali for uric acid stones. But, there is an almost exact parallel situation for calcium phosphate stones, yet such certainty as pertains to uric acid stones certainly does not exist.


Do We Need a Trial for CaP Stone Formers?



We Know the Chemistry

Calcium cannot combine with mono-valent phosphate but only with the divalent form. The pKa for dissociation of the second proton of phosphoric acid is about 6.8 in urine, although the precise value varies with ionic strength. Given the molarities of total phosphate, calcium, citrate – which binds calcium – and other ligands that have modest effects, the supersaturation of brushite – the usual initial urine CaP phase – can be calculated as well as we can calculate the supersaturation for uric acid.

Like uric acid, phosphate and calcium are abundant in urine, so the amount of crystal that can be produced in a day is similar to that of uric acid. Therefore stones can, and do, form rapidly and become large.

As in the case of uric acid, high urine CaP supersaturation can produce snows storms of crystallization; though certainly not common, patients can recognize this as white urine.

On physical chemical grounds, to lower CaP supersaturation below one and keep it there is to prevent CaP stones as surely as one prevents uric acid stones by raising urine pH and lowering supersaturation below one. Why, then, is not this treatment as self evident as alkali for uric acid stones?

Everyone Does Not ‘Know’ Treatment Works

We have no drug corresponding to alkali.

We can raise urine pH safely but cannot lower it.

Acid loads raise urine calcium losses and can be detrimental to bone mineral balance. Higher protein intake is a possible way to lower pH, but not all kidneys respond to acid with a prompt fall in pH. In some cases urine ammonium ion excretion will rise. In others, acid retention may occur. Urine calcium will tend to rise.

So treatment is not as transparent as for uric acid.

But Treatment Must Work Exactly the Same Way

We can lower CaP below 1 with fluids and measures – reduced diet sodium and thiazide – that reduce urine calcium, and we can monitor supersaturation as we monitor urine pH and uric acid supersaturation.

Furthermore, patients can tell if white urine has ceased.

Moreover, because stones are often actively forming, effective treatment is reasonably obvious.

However, these measures may be difficult to achieve. Thiazide is not always tolerated, reduced salt diet not always maintained.

Citrate is a powerful inhibitor of crystals, and it would be good to know if it were beneficial for the CaP stone former.





  1. Mario

    Dear Dr. Coe.
    Many papers state against Potassium Citrate in patients with impaired renal function, but I haven’t found a cut point; so, what GFR level or KDIGO stage is safe for it?

    • Fredric Coe, MD

      Hello Doctor, Personally I have never seen hyperkalemia from potassium citrate in Stage 3, even 3b CKD. Stage 4 is a different matter, and I rarely have used it for such patients. Uric acid stone formers often have stage 3 CKD and I have used it many times. One thing, though, I do a one week fasting renal panel just to be sure. For patients taking an ACE or ARB I start low and check in a week. Regards, Fred

  2. Mark W

    Thank you your work. As I sit here getting up the courage to call the surgeon to begin the process of my 4th surgery for 99.4% calcium oxalate kidney stones, I found your page. I drink at least 1/2 gallon of water per day, eat a low carb diet favoring turkey, spinach, chicken, broccoli, cauliflower, beef, salads. I drink a turmeric/ginger tea regularly. I take 5 mg of lisinopril daily to combat the stones, and I pass usually 2 kidney stones per month… sometimes more and sometimes it seems like I haven’t had kidney stone related pain in a few months… can you please comment on adding insoluble fiber to my diet, and/or taking any type of supplement to help me pass them sooner before they get so big, or any other ideas will be greatly appreciated.

    • Fredric Coe, MD

      Hi Mark, since you form nearly pure calcium oxalate stones, treatment depends entirely on the 24 hour urine and blood testing. Here is a reasonable approach. The very worst approach is to assume or alter diet without information and a plan. Take a look and see if you have been fully evaluated. If not, get it done so prevention can work efficiently. Regards, Fred Coe

  3. Casey C

    Dr Coe
    I have hypocitrauria with an increased PH and low magnesium on a 24 hr stone risk. It says I have high Brushite and high sodium urate in my urine presumably that’s what my stones are. Note: I have passed over 5 stones in the last 2 years and currently have 8 in my kidneys. 2 that measure 5mm and 2 that meas 3mm the rest are smaller. This all started during pregnancy and since I’ve have my daughter who is almost 2 years old. What is the best way to treat these stones and how to prevent them?
    Thank you

    • Fredric Coe, MD

      Hi Casey, Lets begin with the actual stone analyses. You need to know, and since you passed 5 of them no doubt some have been analysed. I imagine they are indeed calcium phosphate, either brushite or hydroxyapatite. The high urine pH is part of the cause, usually high urine calcium is another part. The low magnesium is not obvious – often this is from diet issues, but I lack enough detail to help there. If all you have is low urine citrate and high pH, and urine calcium is normal, potassium citrate may help or not. It can raise urine pH and may or may not raise urine citrate. Are you forming more new stones or passing stones that formed while you were pregnant? Here, your physician has a main role. With all these ifs it is clear that there is not enough information for me to help much. Perhaps you might want to post more of it. Regards, Fred Coe

      • Casey C

        Thank you Dr. Coe for answering my post. I have never had a kidney stone analyzed because I have never caught one or saw one but have passed tissue and blood and had confirmed by doctors ultrasounds that I have indeed passed some. I do have a normal calcium urine result. I passed 2 while I was pregnant then passed 3 more right after I gave birth. Went to the urologist they scanned 5 in my kidneys. 6 months later they scanned 8 so I keep forming them and may still be passing some from being pregnant I don’t know. What is confusing me is the high sodium urate with brushite. It seems that treatment for these would contradict each other. Another note: Last few urine samples from primary care doctor results had a 6.5 PH so my PH has come down since my stone risk last year.
        Thank you

        • Fredric Coe, MD

          Hi Casey, You are confused by the supersaturations; sodium urate and brushite saturations rise with pH, but this may have nothing to do with your stones. You cannot treat high urine pH, but you can lower urine calcium. Do you know your urine calcium and sodium excretions/day? Regards, Fred Coe

          • Casey

            Calcium 107
            Sodium urate

            • Fredric Coe, MD

              Hi Casey, your urine calcium is certainly low, so the high brushite SS must be from your high urine pH. I would mention to your physician that repletion of your magnesium – that is low – and simple potassium chloride might raise your urine citrate. It is simple and worth a try. Regards, Fred Coe

              • Casey

                Thank you so much Dr Coe. I appreciate it and your work. Keep on being brilliant.

          • Casey

            Calcium 106
            Sodium 175
            Brushite 2.01 (<2.00)
            Sodium urate 2.78 (<2.00)

  4. Natasha

    Hi Dr. Coe,
    Could potassium citrate help in dissolving pancreatic stones or calcification of the pancreas? I have heard of using trimethadione, but that sounds risky and would require an off-label Rx.
    Thank you for your time!

  5. Stan Blyskal

    Hi Dr. Coe, and thanks for sharing your time and expertise so generously. So after having an ESWL for a Ca Oxalate stone with a 24 hr u baseline oxalate of 50mg/24hrs I started a restricted oxalate diet along with Ca Citrate 250mg with each meal. 6 weeks later the 24hr U Oxalate had dropped to 22mg/24 with a U Ca of 93 and Mag of 90mg/24hrs. I’m pleased but for the rather severe binding effect of the Ca Citrate despite dietary measures. I was wondering if substituting a dose of Mag Citrate perhaps 15cc of the 10mg/cc solution for one or perhaps 2 of the Ca Citrate doses might be a way of maintaining the benefits of the Citrate component and at least some of the Calcium component with an acceptable side effect burden? Thanks again.

    • Fredric Coe, MD

      Hi Stan, I am glad the calcium worked so well for oxalate. I do not know if magnesium will do it but why not try but then get another 24 hour test to be sure the oxalate is still low. Regards, Fred Coe

  6. Nelson Hochberg

    Any advantage of magnesium citrate vs potassium citrate vs postassium-magnesium citrate supplement in calcium oxalate stone formation? What would be the conversion factors from one to the other?

    Thank you.

  7. Francisco Lizana

    Dr. Coe is calcium citrate useful as a source of citrate to prevent calcium stones?

  8. Gordon Rose

    Dr Coe, I take on a daily basis 1) Simvastatin 40 mg, 2) Warfarin 5 mg, 3) Tamsulosin .4 mg, 4) Sotalol 80 mg, 5) Lisinopril 2.5 mg. Would any of these drugs or combination of cause my body to produce Uric Stones? I pass a few small stones occasionally and urination is sometimes less than ideal. Thanks

  9. Gordon Rose

    Dr. Coe, is there a over the counter item that can be taken that can assist in eliminating the formation of Uric stones in the bladder. Thanks

    • Fredric Coe, MD

      Hi Gordon, Uric acid stones always yield to potassium citrate. But you presumably have prostatic disease with retention and that can promote other kinds of stones. Perhaps you might want that fixed. Your urologist know the proper dose of potassium citrate. The article also mentions a starting dose. Regards, Fred Coe

  10. Theresa

    Do you have any information or advice for a carrier of Lesch-Nyhan’s Syndrome (HPRT1 Genetic mutation) regarding kidney stone formation, or other issues that carriers may have?

    • Fredric Coe, MD

      Hi Theresa, I do not have such information as I have not as yet attempted the genetic causes of stones. But I will make some effort to find out. Regards, Fred Coe


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