Supersaturations Match Kidney Stones

Supersaturations Match Kidney Stones

Why we should care if supersaturations match kidney stones?

Because, to prevent kidney stones we must lower urine supersaturation with respect to the crystals in stones forming. This follows from the physical fact that the sole driving force for crystallization – supersaturation – must determine what crystals form.

In turn, that physical fact makes the obvious prediction that urine supersaturations match kidney stones. But this seemingly obvious prediction has a daring quality. Although urine chemistries change with food and the weather, even, kidney stones accrue mineral like any other geological artifact and therefore reflect long term urine averages.

Put another way, physics demands that long term average supersaturations match kidney stones. But we measure here and there, a day at a time. We and the stones sample different things.

So the seemingly obvious prediction that supersaturations match kidney stones really concerns sampling. Do clinical samples, a day or two here and there, really gauge those long term averages that produce the kidney stones?

This is why we should care if supersaturations match kidney stones.

Supersaturation Stores Work as Energy

Solubility

You can saturate a solution easily. Simply stir it with an excess of any substance at a constant temperature, and eventually the concentration of the substance will come to some final and unchanging concentration. By excess, I mean some of the solid phase remains at the end of the process. We call the solution concentration at the end of the process the solubility for that substance at that temperature. No matter how much excess solute remains in contact with the solution, you cannot drive more of it into the solution.

If you perform the experiment with the same solid phase at different temperatures you will find that solubility rises with temperature. You can create the temperature solubility curve for that substance. Such curves have been created and published for many solute – solid pairs. For example, for the stone forming salts in water at body temperature.

Doing work on a solution

Change of temperature

Because solubility rises with temperature, you can heat a solution at the solubility point and dissolve more solid phase in it. Essentially you move the system up on the temperature solubility curve. That does work on the system – heating it. If you take away the heat source, the temperature of the solution will fall. As it falls the solution gives up some of the energy stored in it by heating.

But, if you do it slowly and carefully, if you lower the temperature back down slowly, the solution it may remain clear even though the concentration of the salt is above solubility. Some of the work you did in heating the solution remains as energy stored as supersaturation. This free energy of supersaturation will eventually release itself by forcing the dissolved salt into a state of lowered entropy – as a solid phase as opposed to a dissolved phase.

Evaporation

Suppose you return to the solution at solubility and pour off the clear part leaving behind the extra solid phase. Keep the temperature constant alone but evaporate water off the surface. For example, fan it, or blow warm air over the water taking care not to heat the solution. Do it slowly and the solution will shrink in volume but remain clear.

Once again, you did work on the solution, and part of the work transformed into the free energy of the supersaturation.

Kidneys do not evaporate water. They use free energy from metabolism of substrates to power transporters that move ions and therefore drive movement of water from tubule fluid back into the blood. Though the pathways are specific to kidneys, they do what you did when you evaporated water: store free energy stored in fluid as supersaturation.

Clinical Urine Samples

We let them cool yet they stay stable

When we collect 24 hour urines, temperature usually falls from that of the body to that of the wide world. Supersaturation must rise as in your experiment. But surprisingly, for up to several days, a urine will generally maintain very constant concentrations of calcium, oxalate, uric acid, phosphate, pH – all of the key variables that we use to calculate supersaturation. Such constancy makes 24 hour urines practical for patient care. We calculate supersaturations assuming body temperature because of the constancy.

But why do they not collapse into crystallizations?

What lets urines store energy for days on end, when in a simple experiment with sugar crystals form if your shake the container? We transport 24 hour urines on trucks, in airplanes; no doubt people shake them up all the time.

Urine contains abundant and varied crystal retardants

The stability of 24 hour urines far exceeds that of simple salt solutions because of retardants. They delay formation and growth of crystals. Some retardant molecules up kidney stone matrix. The urine proteome contains Most of the kinetic retardants, but we know this vast mix more poorly than the flora of the ocean deeps. We know some of the retardant molecules. We do not know most of them. How they act together to retard crystallization remains for brave and tireless scientists to discover. Clinicians have no assays.

But we do know one small molecule, citrate, retards crystals. We measure it, we can influence its urine levels. Citrate links urine crystal retardants to clinical practice.

Do Supersaturations Match Kidney Stones?

Types of Kidney Stone Formers

Our Subjects

With considerable effort, we gathered together our 1085 patients with reliable kidney stone analyses and grouped them by stone type. But first we excluded those with systemic diseases as a cause of stones leaving 585 to ask our question from. We had 24 hour urine studies for 67 normal – not patients – people to use as a contrast.

How We Named The Types of Kidney Stone Formers

Calcium oxalate (CaOx) stone former meant CaOx comprised more than 80% of the total crystal composition of stones analysed from a patient and no stone contained any uric acid (UA).

We named as calcium phosphate (CaP) stone formers those in whom calcium phosphate comprised more than 50% of kidney stone crystals. By contrast, mixed CaP/CaOx stone former meant that CaP comprised between 20 and 50% of the crystals, the rest CaOx. Uric acid meant stones were entirely composed of that crystals, while mixed uric acid meant any uric acid in a calcium oxalate stone.

What We Compared

We have always obtained three 24 hour urine samples from each patient before starting treatment. We used these samples to calculate the three supersaturations – CaOx, CaP, and UA, and compared the values of each between the various types of stone formers and in contrast with our normal people.

Supersaturation vs. Type of Kidney Stone Former – Males

Male SS vs stone composition 3 d plot

Read this 3D Graph With Me.

The pin ‘M normal’ represents normals on three scales. The point of the pin is at about 1.3 SS for uric acid (runs along the front of the graph) and 1.7 Brushite (calcium phosphate) SS. The height gives the calcium oxalate SS – about 9.

Use this as a reference point. M means males, and all pins are males, so I will skip the ‘M’.

Supersaturations Match Kidney Stones

Look at CaP – calcium phosphate stone formers – at the upper left. The pin point lies at nearly 2 on the brushite SS scale and nearly 0 on the uric acid scale but the height – calcium oxalate SS nearly matches the normals. This means a higher CaP SS goes with CaP stones.

Next to it, to the right, ‘CaP/CaOx’ means patients with a lot of CaP admixed in their CaOx stones. See where the pinpoint lies at CaP SS over 2, which matches for abundant CaP in CaOx stones. But the uric acid SS is higher because the urine pH is not as high as the CaP stone formers.

Now, look down at the ‘CaP RX’ pin. See how short it is? That is from treatment. But even though I – these are my own patients – lowered CaOx SS the CaP SS (pin point) lies at nearly 2!

Uric acid stone formers are at the lower right – very short and stubby, treated or not. UA, untreated uric acid stone formers have a uric acid SS of nearly 2 and, of course, a brushite (CaP) SS of only 0.5. Treated (UA RX) their UA SS is near 1. Those with mixed CaOx and UA stones lie far to the right at a UA SS of nearly 2.5. See high tall a pin represents them. They have considerable CaOx SS. Treated, their pin shrinks down and moves to a UA SS just about 1.

Finally, CaOx SS of CaOx stone formers is a bit higher than normals, and when treated their pin shrinks down a lot. But kidney stone formers’ CaOx SS does not exceed normal.

Urine pH Displays Considerable Stability over Time

Stones accrue mineral over long periods as compared to the single day of a 24 hour urine collection. Even so, with some modest variability, the pH dependent 24 hour urine supersaturations tracked reasonably well with patient stone types. This can only mean that urine pH, the main factor that controls CaP and UA supersaturations, remains more or less stable within individual patients over the geological time scale of kidney stone production.

Do Women Differ From Men?

No

Female SS vs stone composition 3 d plotCapture

Just like men, CaP stone formers cluster at the upper left and UA stone formers at the lower right, meaning that supersaturations match kidney stones. Treatment that reduced kidney stone production lowered supersaturations as one would expect.

Yes

But unlike the case in men, calcium oxalate supersaturation of calcium oxalate kidney stone formers exceeds normal.

This sex difference arises from something the graphs do not show. Male calcium oxalate kidney stone formers produce higher urine volumes than normal men. Women display no such urine volume difference.

Adjust for Urine Volume

 

pH Independent Supersaturations – Males

At a glance, the CaOx SS of patients did not differ from normals. But – not shown on the graph – male CaOx stone formers produced higher urine volumes than normal men. How do you manage to analyse such conditions?

 

By contrast, calcium oxalate supersaturation of male CaOx stone formers did not differ from that of normal males (M normal), yet the stones were predominantly calcium oxalate by selection. Here is a paradox, and an important exception to what would seem an invariable rule. In physical chemical terms, supersaturation is the driving force for crystal formation, and there is one physics, so what applies in the closed and narrowed environment of a laboratory experiment applies in humans. But the lack of difference of supersaturations points to the necessity of assuming other important factors intervene between the driving force and its expression.

An obvious candidate is the myriad of urine crystal modifier molecules I have discussed above and in the post on stone matrix. This is a working hypothesis that has not been testable until the advent of proteomic methods that can sort out and quantify these molecules in patients and normal people and begin to show in what ways they might diverge from one another.

Another possibility is that calcium oxalate is itself not an initial crystal phase even in stones in which it is the predominant crystal. Future posts on this site will bring forward evidence about this idea, which is gradually acquiring some support: An initial calcium phosphate deposit is required to anchor the nascent calcium oxalate crystal on the papillary surface. The clinical implication of the idea, if true, is obvious. It would be important to control not only calcium oxalate but also calcium phosphate supersaturations in calcium oxalate stone formers.

One important point of the figure, however, concerns the average supersaturation of treated calcium oxalate stone formers. It is much lower than normal, and lower than pre-treatment. On the whole, treatments for calcium oxalate stones such as fluids, thiazide, and potassium citrate are effective and we use these conventional treatments as do other groups; so the lower supersaturation is in a group of patients whose stone rates are lower than they had been before.

Are women different from men?

Female SS vs stone composition 3 d plotCaptureThey are. The adjacent figure follows the exact form of the prior one but differs in its content. The pH dependent supersaturations, for calcium phosphate and uric acid are higher in patients than in normals, as in men. But unlike the case in men, calcium oxalate supersaturation of stone formers exceeds normal. So women do not pose the calcium oxalate anomaly men pose; the stone formers are more supersaturated with respect to pH dependent and pH independent crystals. This may well be clue, long term, to real differences in the biology of stone formation.

But even though the anomaly is not present, these data are all mean values. The tables from the original paper make clear that these means, as is always the case, are accompanied by considerable variability as evidenced by standard deviations. In other words it is not hard to find a man or a woman stone former whose urine supersaturations fall within the range of same sex normal people.

What should we do?

We treat patients every day, and it may take years to clarify all of the factors involved in stone formation. But we can measure at least this one factor, supersaturation, and know that in measuring it we are observing a principle physical driving force for crystal formation. How we can best use supersaturation given the gaps and irregularities I have shown here is not completely obvious. But to me, the most sensible approach has been articulated by my colleague Dr. John Asplin: ‘The supersaturations of active stone formers are too high with respect to the crystals in their stones and should be lowered’ (Personal communication). He proposes lowering them by half, and that seems as reasonable as any other quantitative proposal.

To use his proposal we need to know three things: the crystals in the stones formed; whether a patient is an active stone former; and measurements of urine supersaturation that are clinically relevant.

Crystals in stones formed

I have already emphasized the key importance of stone analysis and in fact of even sequential and ongoing analysis. Here is more of the argument for such a course of action. You cannot use supersaturation except in relation to crystals in stones, so knowing those crystals is of primary importance.

Is the patient an active stone former?

What is meant by active and what one does to determine activity are hardly the same. Active is by way of metaphor – ‘forming new stones under the present conditions’ would be a kind of translation into something one might attempt to measure. But in reality we mean by new stones those passed or removed or appearing on a radiograph and not present on a prior radiograph. Think about that. The timing is entirely in relation to what images we have available. CT scans are most reliable for counting stones, but entail consequential radiation exposure so we limit them. Therefore there are appreciable gaps, and altogether a determination of activity is rough at best. My view is conservative; if stones seem active, I consider them so and act accordingly.

Are supersaturation measurements relevant?

The case I included in my account of how I practice illustrates the problem. My patient was a nurse with a complex work life and therefore variable hydration and diet. What 24 hour urine should I take as germane? In the case, I assumed what I was receiving – weekend collections – were not relevant, and worked out a way of proceeding with treatment and with correspondingly usable urine collections. Often we have to regularize diet and fluid habits before we can even make measurements to rely on.

This is an area in which patients have to help us to help them. They know their own lives, and they know when a collection is valid or simply what can be accomplished over a weekend off. It is up to us to understand the problem and understand their lives. It is up to them to be sure, once informed about the issues, to get us representative samples under conditions which they themselves believe will be achievable long term and reliably over the working week.

This is also an area in which clinical acumen reigns supreme, wherein the finest physicians may earn their crown imperial. Nothing less will suffice than a full understanding of the patient and the life lived, habits truly followed, motivations feigned and real, desires articulated and desires powerful enough to alter the warp and woof of daily living. It might be said, if I were given to an extreme of expression, that it is in assessment of stone activity I am, at least, most a physician in this odd, technical, and demanding corner of medicine.

Return to Walking Tour on Supersaturation

 

16 Responses to “Supersaturations Match Kidney Stones”

  1. Satyarth Kulshrestha

    Dr Coe, How is supersaturation calculated from a 24 hour urine sample?
    Thanks
    Satyarth

    Reply
  2. Kori isfeld

    Dr Coe,

    What if susperstation Caox and Cap are both LOW as well as urine calcium but you still are an active stone former? I am specifically referring to Cap stones.

    Reply
    • Fredric Coe, MD

      Hi Kori, Since crystals follow physical laws and there is only one physics what you describe is complex. When you say supersaturations are low, compared to what? For example, in some people any CaP supersaturation is enough to create new CaP crystals. In anyone, any supersaturation is enough to support growth of existing crystals, and such new growth can break off and create ‘new’ stones. For this reason, if you are active with ‘new’ CaP stones perhaps SS for CaP needs to be below 1 in a 24 hour urine but so low in 24 hour urines that during the day it is not above 1 at any time. I have not said that on this site before, but it is crucial for practice and I really should add the point in the articles. Regards, Fred Coe

      Reply
  3. Jacob

    Hi I am a patient and chronic calcium stone former. I found this site when trying to determine how I might be able to improve things. My urologost and I have struggled to manage things over the last few years as I am always producing and passing small to medium size (5mm) stones. While your language is geared towards medical professionals I found your analysis interesting and relevant.

    Reply
    • Fredric Coe, MD

      Hi Jacob, I guess the most valuable way to progress matters is to think about a strategy for prevention. I have several linked articles on this topic, and this link ‘links’ to them all. Basically you need to know the crystals in your stones, know the supersaturations in your urine that are relevant to those crystals, and take steps to lower them. Have a look and let me know. Regards, Fred Coe

      Reply
  4. Raj

    Whether the stone is soluble when we maintain concentration below supersaturation in urine? Or it is irreversible? . I have 2 cm size kidney stone in right side.

    Reply
    • Fredric Coe, MD

      Hi Raj, uric acid and cystine stones can and do dissolve. Calcium oxalate stones hardly ever, and calcium phosphate likewise. Regards, Fred Coe

      Reply
  5. markhaddin

    The stability of 24 hour urines is far greater than that of simple salt solutions because of its retardants which are, at least in part, the molecules that make up stone matrix.

    Reply
  6. Joseph Skulan

    There is a geological analog to this. The ocean is supersaturated with CaCO3, but is metastable because of poorly known proteins and other organic molecules excreted by organisms. There are a few places where CaCO3 spontaneously precipitates from seawater, but for the most part it is removed by organisms that exploit the supersaturation to build skeletons.

    Reply
    • Fredric Coe, MD

      There is also a normal human analogue: Blood is metastably supersaturated with respect to calcium monohydrogen phosphate but tissue bound and circulating inhibitors prevent soft tissue crystallization most of the time where as bone exploits the saturation to add new mineral as part of bone turnover. Fred Coe

      Reply
  7. Joseph Skulan

    As always, a clear and thought provoking discussion.

    A few comments from an interested but mostly uninformed observer:
    What I the critical size of oxalate crystals in urine, or of apatite crystals if these are the nucleation sites for oxalate crystals as you suggest they might be? Given the complexity of crystal growth in the presence of many and unknown inhibitors, I suspect that there is no simple answer, but I ask because in my experience the behavior of very small (say <500 nm) crystals is unpredictable, and thermodynamic theory a poor guide. For example Ostwald ripening, in some cases at least, is a thermodynamic fantasy that real crystals don’t obey. Hematite (Fe2O3) nanocrystals incubated in their parent liquor at saturation became finer, not coarser, as large crystals (ca 300nm) preferentially dissolved and are replaced by a new generation of smaller (ca 50nm) crystals. This seems to be because the larger crystals had more and larger defects, which negated the increased stability they otherwise would have had from their lower relative surface area.

    Have there been any isotopic studies of kidney stones? I know that there haven’t been any for Ca isotopes, but perhaps someone has looked at O or C. I ask because isotopes could record information about the kinetics of crystal growth and the actual conditions of growth, which may not be the same as what you see in 24 hr urine. For example, the isotopic offset between total urinary and mineral Ca should be less in crystals that form rapidly than those that form slowly.

    Reply
    • Fredric Coe, MD

      I do not know if there is a critical size for stone crystals because of the extreme pressures that urine proteins exert right from the beginning of nucleation. Much of what we know comes from in vitro modelling which is never really exact in relation to the situation in kidneys. I know about one isotope study in kidney stones by professor Kok using – I believe – calcium isotopes to date stone formation via swings in isotope abundances from atomic testing. With respect to differences between urine and stone I know of nothing. Of course urine conditions vary constantly between people and within a person over time, but perhaps isotope ratios do not vary so this kind of information might be available given stones. Stones are abundant. Regards, Fred Coe

      Reply
  8. Jeffrey Cicone, M.D.

    The article on supersaturation, although academically interesting, does not give specific suggestions on what might be most helpful to patients with higher than average supersaturation of CaOx or CaP. Increasing urine volume will lower supersaturation, but is there any benefit to HCTZ if the patient’s 24 hour urine Ca is not high, or is there benefit to oral calcium or dietary restriction of oxalate if the patient has normal 24 hour urinary oxalate excretion?

    Reply
    • Fredric Coe, MD

      Thanks for such perceptive and useful questions. When urine calcium is normal depends on the definition. I prefer using statistical risk estimates as a basis for deciding when urine calcium is high in a stone former, and that would place the upper limit – when risk begins to increase – at about 200 mg/day. Likewise for urine oxalate, but I am afraid that risk begins at around 25 – 30 mg/day so one is always hoping to lower its excretion rate. As a clinician, like you, I use fluids first, and hope to reduce supersaturations for CaOx and CaP by about half. Often, the amount of fluid required is quite high and not achieved in practice. When urine calcium is not above conventional limits – 250 mg/day for women, 300 mg/day for men – but above 200 mg/day in either sex, I try to lower sodium intake to below 100 mEq/day as a first step and then add a low dose of a long acting thiazide like drug such as chlorthalidone 12.5 mg daily or indapamide 2 mg daily. I always try to raise diet calcium to around 1000 mg from foods, in hopes of lowering urine oxalate and, incidentally, lowering risk of bone mineral loss. Likewise in all cases I look for sources of high diet oxalate. When urine calcium is below even the statistical risk limit of 200 mg/day, I still try to lower diet sodium intake to below 100 mEq/day, but decline to use thiazide like drugs. This is personal preference as we have no relevant trial data. I should mention that the site is in evolution, and sections on hypercalciuria, as a example, are yet to come. One day, when all of it is finished perhaps some of the excellent questions you have posed will be answered more organically. Regards, Fred Coe

      Reply

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