Not all of my colleagues worldwide will agree with me about the primacy of supersaturation in causing stones, but almost all will agree it is very important.
The simple childrens’ experiment of dissolving sugar in warm water and letting it cool is supersaturation at work. When you spoon sugar into water until no more will dissolve and some grains lie at the bottom of the glass, you have made a saturated solution.
You cannot supersaturate it by spooning in more sugar – that is the crucial point. You have to do work on the solution. For example, evaporate water. Or, you can spoon the sugar into warm water. The amount of sugar it will hold when warm is more than when cold. So, let it cool and it will supersaturate.
Kidneys remove water. They filter massive amounts of calcium, and oxalate, and phosphate, all the stuff calcium stones are made of, and let out into the urine whatever they need to for bodily economy. They also conserve water as they need to, and the two – stone stuff and water – are treated independently: The kidneys have no way to know if they are supersaturating, or how much.
Once supersaturated the solution will ultimately crystallize, but when is uncertain. Especially urine is uncertain because it has molecules that delay crystal formation. Your sugar water does not, and it is easy to get it to crystallize.
The article has three big points for everyone to consider. Active stone formers are obviously making crystals, so their urine is too supersaturated. Water is the perfect way to lower that supersaturation. Exactly what your supersaturation is may be is hard to determine.
A nice thing about these tours is that the order of the articles can be any way we want. The place we just saw was among the first constructions on this site. This one is much later, and others intervened. But to me this is the place to visit next.
It is by removing water from salts the kidneys make supersaturation, and it is by adding back water that we reduce supersaturation in precisely the way it was made. The question is always how much water. One might say, if naive, as much as possible. But, in real life, it is trouble to drink more than a few liters daily so we want just enough for safety.
Where we will now visit is an article which shows supersaturations in stone formers and normals under controlled conditions so we can inspect how supersaturation changes with urine volume. Because they excrete more calcium than normals, patients have higher supersaturations at any urine volume – you will see that.
The main finding is that about 0.1 liter – or quart – hourly is a sweet spot. That makes about 2.5 liters a day.
Three other scientists, Dr Jack Lemann, and Drs. Charles Pak and Kashayar Sakhaee found much the same, when all is said and done. Yet another one, not in this article, Dr. Gary Curhan, came to about 2.25 – 2.5 liters a day as a safe place. We will visit him later on today.
Because we lose water breathing and sweating, we need to drink more than that to get 2.25 to 2.5 liters of water. About 1/2 to 1 liter more is probably right for people mainly indoors or during winter. In summer, the amounts are larger.
Another main finding is about moonlight.
By night we drop urine volumes a lot, and in stone formers and normals supersaturations rise. I believe stones form then, and wise prudent people should drink enough to get up once so the volume flow is not so low. There is no trial to support my prejudice. But here, on a walk, why not say what I believe?
I feel like my tour seems to have taken you to visit three rather similar castles, but they are not the same. The first was a whimsy place and the second an all out fancy one, with all its details about supersaturation and fluids.
This one is practical to a fault – like one of those medieval moated castles meant to stave off attackers. No frills, but useful for defense.
And it is defense we are after.
The article is long and in parts.
The opening parts reiterate the supersaturation hypothesis, and take on the two easy cases: Cystinuria and uric acid stones. For them supersaturation and stone formation are one to one. For uric acid the link is so strong one might say there is little excuse for another such stone once someone comes to a physician.
What comes next looks elaborate and technical but is not so hard to understand.
Supersaturation that arises from salt concentrations – calcium oxalate, calcium phosphate – is determined by a lot of alternative ways the key constituents (calcium oxalate and phosphate) can bind with each other and with other urine molecules. So we need to use a computer and make many more measurements than just these three.
Likewise, we needed, long ago, to choose a practical means for measurement and adopted the 24 hour collection. It has the virtue of being one collection and an average over a day and night.
It has the disadvantage of being an average when the reality is peaks and valleys.
The next big section shows these peaks and valleys so you can be aware of them in planning fluids. We already showed you fasting, meals, and overnight; here is more detail, and it is not only supersaturation we show but the materials that control supersaturation – what you can alter with diet and – if needed – medications.
Urine volume, calcium, citrate, oxalate, phosphate, pH, uric acid, and the supersaturations all make their appearances.
It is a pageant. Look for your own stones, or if a physician the problems presently of interest to you.
The next part introduces the brilliant work of Dr. Gary Curhan, a professor at Harvard who has delineated stone risk association to key measurements: excretions of water, calcium, oxalate, and citrate in 24 hour urines. I have summarized his main points in a graph, and from it you can gauge stone risk from how much you lose in the urine.
Finally, if not exhausted, see the last part on whether to collect one or two 24 hour urines for planning treatment. I mount a passionate and well supported argument for two.
I know this article is long and it can look overly fussy and academic.
It is not.
It is perhaps the most practical kind of article for physicians and interested patients. It contains and presents the real facts, in patients, about the main things that are treated in stone prevention. How nice is that?
Even if you are totally worn out, this brief article is worthwhile for a few moments.
It does not have the stature of the two serious articles we have just explored nor the charm of the sugar crystals. It was put up early and meant to show how powerful supersaturation was in predicting the kind of stone crystals a patient might be forming.
Stone analyses are not always available or reliable. From the 24 hour urine supersaturations one can make an reasonable guess.
But on a higher level, the matching of supersaturations to stone crystals gives one a sense that these complex calculations are reflective of a reality, of those free energies in the urine a patient produces that have given rise to crystal formation.
When we wrote this paper I found it astounding that stones, glacial relics of perhaps years of life, are correlated at all with supersaturation derived, in our case, from three 24 hour urines taken before treatment is begun. I remain astounded years later.
This is the first place I enunciate the primary maxim of clinical supersaturation: The urine supersaturation of an active stone former is too high with respect to the crystals in the stones. That maxim can only be used in practice if patients will do their part, and if physicians do theirs. So for that reason alone this modest contribution warrants a serious if brief stopover.
The Maxim demands: We know the stone crystals; we know the patient is an active stone former; we know the supersaturation reflects the reality of the patient’s life. Nowhere else on this site has the maxim been so fully articulated as here, and expressed in terms of what it means to be a clinician.
We are in Slovenia. Across the Adriatic is Venice, above is Austria and to the south Hungary.
While we eat is a good time to enjoy two wonderful articles by Jill Harris on how to drink: The one is about how much, the other is about what is on the menu. These require no exposition, and like Jill herself are filled with light and charm.
Jill wrote another one, by the way, much less visited than it should be. It reiterates the primary maxim of clinical supersaturation in her delightful manner of putting things and considers the problems of collecting urine responsibly: Representative of real life and therefore worthwhile. Take a look.
The air is brisk up in the hills and needs to be. The next place is scary. Supersaturation is a big topic and we need at least one glimpse of how it looks in reality.
The article centers around a publication by a heavy scientific type who presents supersaturation as it should be presented. Clearly physicians and scientists can follow the presentation. But I do not think the material is not beyond what many non technical people can understand.
The picture of the Moirai, or fates, is because once supersaturated a solution will ultimately produce s solid phase; that is its inevitable end. It is only when that is, so to speak, ‘free’ and undetermined.
The urine has many defenses against crystals, but they can only delay things. Because urine leaves the kidney in a timely way delay is a powerful defense, but clearly not always enough.
Why look at such a detailed paper? It is because it is the reality of supersaturation. Not an image of it, a metaphor, a mannered summary, but how it is. I think for everyone who can stand to look at it, reality is soothing, stable, the bedrock on which everything else is founded.
Two brief reviews of related papers follow, and I would not be miffed if you glance and move on.
This is a hard afternoon.
The article takes up from the Ostwald limit – the supersaturation where a solution erupts into crystals, and explores the importance of citrate in controlling the height of that upper limit.
No article I have written surpasses this one in length and complexity, nor in importance, because unlike any other inhibitors in urine citrate can be manipulated and therefore protection brought about in some cases.
Potassium citrate is a clumsy pill, big, expensive, and seemingly simple.
It is not simple.
It exerts a massive effect on the cell biology of the kidney and on the functions of kidney cells because regulation of acid and base balance is a fundamental part of the biology of all cells, ours included.
The effects of the pill are on urine citrate, among other things, and citrate appears to be a main regulator of when a urine will in fact give way and crystallize.
The analysis in this article can be found nowhere else. If you can stand to read it, you have the best I can offer on the subject right now.
For physicians and scientists interested in stones, I call this a very interesting place to dwell a while. For patients, it is a glimpse of why the large, clunky pills are worth it all. They seem almost trivial, a mere potassium salt, but they are much more.
I headed the work with the beautiful and rather strange tune of Simple Gifts, because it speaks about a middle place which seemed to me a fair trope for the metastable zone. But I meant more than I said. How kind of evolution, how brilliant, to make such a compromise between the needs of mineral homeostasis and water conservation, a compromise just sufficient to preserve kidneys under difficult circumstances.
My only personal memoir takes its theme from the magnificent and unfinished Art of Fugue. In it, Bach presents 14 fugues and 4 canons on a single theme and in them illustrates virtually all aspects of that recondite form. The last fugue was unfinished at his death, incidentally,
I mean not at all to compare my humble work with such towering genius but simply to say that clinical practice is a kind of art, bettered by repetition and by offering it its due time.
The article speaks about how I practice my trade but of greater importance puts forward a case that illustrates the main points about representative 24 hour urine collections and the interpretations of such testing in real life. In other words the case illustrates the maxim in practice.
My patient was no niaf but rather a skilled nurse with considerable savvy. Even so we had a tough go at it before we could get things together between us and get rid of her stones. The maxim is difficult but to me it is essentially all we really have.
Fred Coe, your tour guide.