Chapter Eight: Uric Acid Stones

Uric acid stones, to me, means not just pure uric acid stones but any uric acid in stones. If this seems fey, let me explain. Uric acid is a peculiar kind of crystal. Low urine pH causes them and treatment that raise urine pH prevent them altogether. Whether they form combined with calcium stones or pure, treatment is the same.

Why then scruple over percentages? If I find uric acid in any stone, I look at urine pH with a yellow eye. Should it be low I treat it surely and on the moment so at least that crystal be banished forever.

The Profligate Punished by Neglect, Edward Penny 1774 catches the common motif of diet excess, obesity, diabetes, and gout – the joint manifestations of uric acid crystals. Note the abdominal fat denoted by his overly tight vest. All of these states can lower urine pH and lead to uric acid stones.

This article has a pragmatic leaning and eschews excessive scientific details. I have written a more mechanistic article that explores how the low urine pH might arise and cause uric acid stones. Read this one first unless you are already reasonably expert.

Who Are Uric Acid Stone Formers

Stone Analysis

Given my prior reasoning, I call patients who have any uric acid in their stones uric acid stone formers but reserve the right to use compound names when needed. If all stones are only uric acid, I call such patients pure uric acid stone formers. Those whose stones contain uric acid and other crystals I call mixed uric acid /x stone formers: mixed uric acid calcium oxalate, mixed uric acid calcium phosphate stone formers, as examples.

These niceties of naming have the practical value of calling to mind the perpetual need for dual or multiple treatments – for uric acid but also for whatever crystals might be present.

Radiographic Evaluation

Commonly uric acid stones show poorly on routine flat plate x rays having only carbon, nitrogen, oxygen and no heavier atoms such as calcium. On CT scans they do not look different from calcium stones but radiographic density can be measured and tends to be lower. As this article points out, machines differ in their results and evaluation may therefore be less than perfect. Dual energy scanners are more precise, but also prone to many potential artefacts. Multiple reports, by contrast, indicate that CT measurements of radiographic density can reliably distinguish uric acid stones from calcium stones.

A reasonable present view is that lower radiographic density is an excellent clue to uric acid in stones, but far from definitive as stone analysis is. I hesitate to classify a patient on scanning evidence alone.

Signs and Symptoms of Uric Acid Stones

Pigmented Stones and Crystals

Being stones, uric acid stones cause the usual problems of pain, obstruction, bleeding and infection. But they have some special features. The most obvious is stone color – red to orange because the crystals take up a variety of pigments mostly derived from hemoglobin breakdown. Recently scientists have determined the structure of one of these – urorosein.  Sometimes, coarse or fine orange or red gravel passes, made up of uric acid crystals.

Rapid Crystallization, and Stone Growth

Because the crystals form not as a complex lattice like calcium with oxalate or with phosphate but simply as uric acid crystallizing with itself, the process can be swift to begin and require very little supersaturation. Said more technically the energy required to create the crystal is relatively low. This means the upper limit of metastability – the supersaturation needed to initiate crystal formation is not far from solubility, so values above 1 even if below 2, could suffice. Practically it means that bursts of supersaturation during the day can bring on showers of gravel and growth of stones.

Also, urine contains a lot of uric acid. Common daily losses of oxalate approximate perhaps 25 – 50 mg, compared to 600 – 1,000 mg of uric acid. The sheer amounts available when coupled to the rapid and facile crystal formation and growth allow stones to enlarge rapidly and achieve very large sizes, enough to fill the renal pelvis and calyces – so called staghorn stones.

Acute Uric Acid Nephropathy

Very uncommonly, sudden lowering of urine pH coupled with low urine volume can cause crystallizations in the terminal collecting ducts with acute kidney failure. This was once not uncommon during treatment of malignancies, but modern attention to uric acid surges from tumor killing has made it rare indeed. Today, one does not expect to see it apart from unusual situations

Uric Acid Supersaturation

I made the figures for this section anew but from a lovely data file constructed some years ago by Joan Parks, who was my scientific colleague from 1976 until her retirement about 8 years ago. Her legacy of curated data files sustains a lot of my public writing, now, and she deserves a place in it. 

Effects of Urine pH

Uric acid crystals form like all crystals because of supersaturation. In this instance, that supersaturation varies remarkably with urine pH.

In the figure, supersaturation ranges from 0.01 to 10 fold. The dashed line at 1 represents equilibrium, or saturation, the level where crystals neither form nor dissolve. The horizontal axis shows urine pH. The dashed lines at 5.5 – acid urine and 6 neither acid nor alkaline urine are for visual reference.

The tiny points each are one 24 hour urine from patients and normal people. Like an ancient Persian scimitar, points curve downward from 8 to 0.03 as pH rises from 4.5 to 7.5.

Effects of Urine Volume

Urine volume matters. Low volumes (red) 0.5 to 1 liter/day give higher supersaturation than 1 to 1.5 liters/day (green), and 1.5 to 2 and above 2 liters/day (blue and black) lower supersaturation progressively.

But pH trumps volume. At pH 5.5, the whose distance from red to black varies supersaturation between about 2 and 5 fold (use the lines for averages) whereas raising pH from 5.5 to 6 brings almost all the points down below 1. Below 5.5 virtually no points are below 1 at even above 2 liters of urine volume daily.

Effects of Uric Acid Excretion

In speaking about excretion of uric acid we need to insert a note about the molecular species involved.

Form of Uric Acid in Urine

Uric acid is a weak acid, which means it can take up or donate a proton to water. When it has its proton, that proton neutralizes much of its charge, so water molecules cannot themselves form charge bonds with it to keep it in solution. This means that the molecule becomes very poorly soluble and tends to crystallize.

When it loses its proton into solution, it has a charged site for water to relate to and also requires a counterion, which in urine will be sodium, potassium, and ammonium ion. These ‘salts’ of urate – the name for uric acid when it has given up its proton and is a charged ion – can themselves form crystals just like calcium and oxalate form a salt – calcium oxalate – that can crystallize. But all three salts have much higher solubility than uric acid itself.

Effect of Uric Acid Excretion on Supersaturation

When we measure and report urine uric acid excretion we show the sum of all salts and the acid in one number. Obviously this total should affect supersaturation, but the effect is relatively small because so much depends on pH that sets the percentage of uric acid per se – the fraction that has its proton and is therefore poorly soluble.

Here, red, green, blue and black stand for below 500, 500 to 750, 750 to 1,000, and over 1,000 mg/d of urine uric acid excretion respectively. As for urine volume, the total amount of uric acid matters; a fivefold increase from below 500 mg to over 1,000 mg/day raises supersaturation at pH 5.5 from about 1.2 to about 3 fold.

Urine pH of Stone Formers

One presumes that urine pH of uric acid stone formers must lie below that of other kinds of stone formers, and numerous reviews and case descriptions have proven this true.

My own collected data make the point as well as any.

The dot distribution just below shows individual 24 hour urine pH measurements for calcium oxalate (blue), calcium phosphate (green) and uric acid (red) stone formers. Here I include among uric acid stone formers those with both pure and mixed stones.

Calcium oxalate stone former pH ranges widely with an average at about 5.8 pH units. Calcium phosphate stone formers average a lot higher – around 6.4.

Uric acid stone formers lie in an acid range. Their average is about 5.3 – 5.4 and only a tiny scattering of points range above 6. So uric acid stone formers produce a very acid urine compared to other stone formers, and the pH is exactly in the range to produce supersaturation that can drive formation of uric acid stones and hold them steady or cause them to grow.

To see this, just look back on the graphs showing supersaturation vs. urine pH. Below 5.5 values almost all lie above 1 – solubility – meaning that crystals can form and grow.

UA Fraction in Stones

The General Pattern

I have said that any uric acid in stones means pH should be raised because at least that portion of the stone burden might dissolve or at leasts not grow.

The figure below shows urine pH associated not with the kind of patient – calcium oxalate, calcium phosphate or uric acid stone former, but by the fraction of a given stone made up of uric acid.

Blue means no uric acid at all. Red means 100% of the stone is uric acid, and pink and green lesser amounts. With a scattered few points as exceptions, stones made of mainly uric acid go with urine pH values mostly below 5.5.

The graph makes a point we often speak of but rarely show. Oxalic acid has a very low pKa – is a strong weak acid. So it has charges available for binding to calcium that very hardly at all with urine pH all the way down to 4.5, about the lowest value human kidneys attain. So these stone crystals are indifferent to pH.

Paucity of Mixed Stones

I makes another point, too, one that a patient emphasized in a comment to this article and that I failed to mention in the original version. Of all stones that contain any uric acid, at least in my collection of data, most are mainly composed of uric acid. See where the red – pure uric acid – stones make up the largest mass in the figure just above?

This is not to say that patients are uncommon who make both calcium and uric acid stones – mixed stone formers. The graph shows the stones themselves. People who make both kinds of stones need treatment with alkali so they will stop making uric acid crystals. They also may need treatment against their calcium stones. Stones that contain both uric acid and calcium – usually calcium oxalate – mean the patients may need treatment against both their uric acid stone formation – that would be alkali, and for their calcium stone forming.

So in the final analysis, whether the stones are mixed, or patients form both uric acid and calcium stones the answer is the same: Treat against both crystals.

Who Produce Uric Acid Stones?

Low pH Without Intestinal Disease

Genetic Factors

In identical twin studies, urine pH had only a 60% concordance compared to over 90% for calcium excretion. In a larger study urine pH seems as heritable as urine calcium excretion. Of interest, such dietary traits as sugar, calcium, and protein consumption that could influence stone formation also had significant heritability.

Systemic Disorders

Historically, uric acid stones have been linked to gout. A recent but brief review repeats that fact. Likewise, another review.

Given low urine pH drives uric acid crystallization, one has to ask whether some kinds of patients might be expected to produce acid urines. In answer, those most common are obese, older, diabetic, hypertensive, and prone to modest reduction of kidney function. Obesity itself, without necessarily overt diabetes correlates with lower urine pH in a progressive manner – as obesity increases urine pH falls

Resistance to the actions of insulin – so called insulin resistance – is often invoked as a general paradigm to encompass the general class of abnormalities that lower urine pH. Metabolic syndrome, a mix of insulin resistance with lipid and vascular abnormalities is linked to kidney stones. But not to uric acid stones per se. Attempts to link uric acid stones to gut bacteria – use of the genetically defined biome -failed in a tiny study to disclose any species unique to uric acid stones.

Kidney Physiology

At least one specific abnormality that produces the low pH is an inadequate production of ammonia with which kidneys can remove acid. I plan another article on uric acid stone formation that will review the underlying disease mechanisms, and do not wish to burden this text with more detail. The linked articles from the group at UT Southwestern Medical School give access to the best current work on the subject. Essentially uric acid stone formers respond to acid load with less ammonia than normal people. Insulin resistance probably produces the renal tubule abnormality.

The issue is complex, as illustrated by a recent publication that found no evidence for low urine ammonia in uric acid stone formers. But the conditions of that study – mere measurements made in uric acid stone formers with comparisons to normal ranges hardly have any power to test the ammonia hypothesis.

In an elegant analysis of a single patient, Kamel and his colleagues point out two matters I use in my own work. Urine ammonia needs to be viewed in relation to urine sulfate – the net acid load. Likewise, the low urine ammonia of their case was accompanied by a high urine citrate – this occurs when proximal tubule cells consider themselves in an alkaline state that would cause a fall in ammonia production

I have allowed myself a bit more about the urine pH than perhaps is ideal, and will end here. Either I will write another article on this subject or expand this one with my own data on ammonia and citrate.

Intestinal Causes

Intestinal Diseases

Any organic cause of diarrhea can lower urine pH because the fluids contain appreciable bicarbonate, the main blood buffer. In turn kidneys increase acid excretion in compensation. This requires both an increase of ammonia excretion and lowering of urine pH. Common situations include small bowel resection for such conditions as Crohn disease and partial or complete loss of colon. The latter, ileostomy, can cause marked alkali loss with acid urine and uric acid stones.

Chronic intestinal fluid losses also deplete body sodium and potassium. The 24 hour urine is very valuable for assessing both as excretion rates fall with such losses. Repletion with a mixture of sodium and potassium alkali is often valuable.

Bariatric Surgery

Howsoever valuable, these can result in both enteric hyperoxaluria and chronic alkali loss so calcium oxalate and uric acid stones do occur. The former are more common. This recent and excellent review details new stone frequencies but stone analyses are not widely reported so I cannot state the balance between calcium oxalate and uric acid crystals. Treatment with potassium alkali is recommended to increase citrate and pH.

Overuse of Laxatives

By increasing Gi fluid and alkali losses one might think these drugs would cause uric acid stones. In fact, a recent review of reported cases – not many! – suggests that mainly low urine volumes from fluid loss causes calcium stones. Not uric acid, in fact, but ammonium urate stones have been documented. I presume they represent induction of ammonia production by the potassium depletion from the diarrhea. As ammonia increases urine pH can rise despite loss of alkali and the higher pH would favor the ammonium acid urate salt.

What Happens With Treatment

Changes in Urine pH

In principle, potassium alkali in the proper dose will raise urine pH and abolish uric acid formation. The reality of practice has a bit less perfection.

These are data from my own work.

The original pretreatment urine pH values are at the top of the figure, for reference, in red. Below them, in pink squares the treatment data show a large shift toward high urine pH so that a majority of values lie above the pretreatment ones. But some patients did not take their medications, and in some I miscalculated the dose needed.

Even with this natural variation in physician intent and patient willingness, the shift of pH with treatment was drastic in my own practice.

Given the powerful dominance of pH over supersaturation, I decided to not add a figure showing that supersaturation fell – it would be redundant.

Treatment Complexities

Potassium

Although potassium alkali – potassium citrate or potassium bicarbonate preparations are an obvious and widely used treatment, the kind of patients involved – often older, diabetic – may not tolerate large amounts of extra potassium without increasing serum potassium. Especially, common and effective blood pressure medications such as angiotensin converting enzyme inhibitors or receptor blockers can worsen the risk. Typically most clinicians are aware of the problem and proceed based on serum potassium level and whether kidney function is normal or not. Sometimes I have urine potassium citrate with a low dose of thiazide diuretic – the latter to foster renal potassium loss.

Sodium

In the intestinal diseases, sodium depletion may be great enough one wants to use sodium alkali. I prefer inexpensive sodium bicarbonate tablets bought over the counter, being cheap and easy to use. Two provide about 13 mEq of base.

Dosing

I almost always begin with 40 mEq daily and repeat the 24 hour urine measurements. Spot urine pH testing with pH paper never impresses me as very useful because results scatter and, after all, what most matters is average supersaturation over the day. These crystals can form and dissolve rather rapidly, and one hopes to achieve 24 hour average SS below 1. Overnight is clearly a high risk because of lower urine volumes so a nighttime dose of alkali before bed seems reasonable. If I need to I increase dosing in 20 mEq/day increments.

Effect on Uric Acid Stones

Uric acid in stones has a different meaning than we attach to calcium oxalate or calcium phosphate, or even cystine. This crystal can be prevented by raising urine pH within the common physiological range between 4.5 and 6. This means that simple alkali treatment should and will prevent such crystals in stones. Likewise, lowering supersaturation below 1 must eventually reduce kidney stone mass. Put another way, not guile or special knowledge but simply persistence with alkali use must inevitably stop uric acid crystallization.

Even so, data are hard to come by. This small report says that 91% of 24 uric acid stone formers treated with potassium citrate had no recurrence after a mean of 31 months.

No Formal Trials

A look on PubMed found no prospective uric acid stone prevention trials.

(For the purists, this was my search: ((“prevention and control”[Subheading] OR (“prevention”[All Fields] AND “control”[All Fields]) OR “prevention and control”[All Fields] OR “prevention”[All Fields]) AND (“uric acid”[MeSH Terms] OR (“uric”[All Fields] AND “acid”[All Fields]) OR “uric acid”[All Fields]) AND (“calculi”[MeSH Terms] OR “calculi”[All Fields] OR “stones”[All Fields])) AND Clinical Trial[ptyp])

I am not surprised. Given all we know can we assign such patients to a control group that does not receive alkali? Given the ease of use should one even try to do so?

I say not.

 

32 Responses to “Chapter Eight: Uric Acid Stones”

  1. Debi S

    Thank you, Dr. Coe. I am learning a lot from your articles. I have a VUR reflux which was very bad when I was born. After surgery it got better but still have and cause problems. I started with calcium oxalte stones when I turned 29. I also have sponge kidneys. I just had a new 24 hour urine and it now shows high calcium excretion 1,856, high excretion of uric acid 1,856 and high CIT acid excretion 1,856 and my oxalate was still high 1,775 after 2 weeks on a low oxalte diet. The high acid is new. I am overweight and have hypertension controlled on meds, and I am now 50 years old. I have not passed any acid stones. What should I start doing now to keep from making acid stones? Is there anything I can do with my diet to better my urine ph and acid levels? I already eat low protein, working to get it up with non-meat due to low protein and low albumin. I try to meet my calcium numbers to protect against the calcium oxalate stones.

    Reply
    • Fredric Coe, MD

      Hi Debi, I am confused. Did you have uric acid stones, too? Your numbers are not correct – urine calcium, citrate, and uric acid are the same and that is just a misreading. Check again and feel free to post the correct numbers. Is your urine pH low? Before doing anything, try to get the numbers in order. Regards, Fred Coe

      Reply

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