A Direct Measurement
Only supersaturation can drive crystal formation and growth.
Need for An Interpretive Maxim
But myriads of organic molecules which delay crystal formation and growth, molecules in urine and probably kidney tissue itself complicate and diffuse the natural power of supersaturation over crystallization. They confer on urine the very power to maintain a supersaturation over days or even weeks that allows us to measure supersaturation in a 24 hour collection.
Even so, the urine supersaturation of an active kidney stone former, whatever it may be, is too high with respect to the crystals in kidney stones forming. We need to lower it. This principal maxim cuts through the complications organic molecules produce and guides clinical supersaturation use for kidney stone prevention.
The Three Supersaturations
Calcium kidney stones
In these patients, urine organic molecules most weaken links between supersaturation and crystal formation. As a consequence, clinical supersaturation use depends on the principal maxim.
Uric Acid kidney stones
By contrast supersaturation links so strongly to uric acid kidney kidney stones we need no maxims. Reducing supersaturation below 1 prevents the stones. Nor does anyone doubt that urine pH controls uric acid supersaturation. No one will attempt a formal trial of potassium citrate – which raises urine pH – for uric acid kidney kidney stones. We lack the equipoise to permit a placebo arm.
Cystine kidney stones
This organic crystal forms when urine is supersaturated with cystine because transport defects in the kidneys lead to excessive excretion. Though not easy to measure commercially available urine cystine supersaturation gives reliable results, even despite thiol binding drugs. Clinicians can use this clinical supersaturation assay for patient management.
We have no magic potion to abolish cystine supersaturation. But even so, no one doubts that supersaturation causes cystine kidney stones, and that prevention depends upon lowering supersaturation.
The Components of Supersaturation
Laboratories Calculate Supersaturations
Although one can measure it directly, such tiresome and expensive methods cannot support large scale kidney stone prevention. Commercial vendors calculate supersaturations using updated versions of a program written originally by Birdwell Finlayson whose picture I feature in this article.
What Measurements are Needed?
His program uses 13 measurements (all but pH are amounts in 24 hours): Volume, calcium, oxalate, phosphate, citrate, magnesium, pH, uric acid, sodium, potassium, chloride, sulfate, and ammonium ion.
Vendors usually include urine urea to estimate protein intake, and creatinine to estimate completeness and consistency of collections.
Which Urine Measurements Most Affect Which Supersaturations?
For calcium kidney kidney stones: Volume, calcium, oxalate, citrate, and pH.
For uric acid kidney kidney stones: Volume, pH, and total uric acid excretion. Of these, pH and volume predominate.
For cystine stones: Volume and cystine; pH exerts a small effect when above 7.
As we eat and sleep and work periodically over 24 hours, urine composition and supersaturations track the consequences of our behaviors. So supersaturations vary with how we lead our lives from hour to hour. How can we summarize so much variation in a convenient way for clinical supersaturation use?
Although most practical for clinical supersaturation measurements, the 24 hour urine collection averages these peaks and valleys of everyday life. As a result they minimize the worst of things. Multiple spot urines can track variations better, but cannot support patient care. They cost too much and burden patients with multiple containers. As a compromise, I advocate 24 hour collections but want to know where peaks and valleys usually lie.
I have chosen data from calcium oxalate and calcium phosphate kidney stone formers studied in our clinical research center. All ate the same diet during measurements that extended throughout a full day and overnight. Reasonably well matched controls served as a contrast.
Although their kidney stones contained no uric acid, I include urine uric acid excretion and uric acid supersaturation by way of completeness.
Physicians try to raise it. Patients need somehow to find ways of drinking enough and not go mad. Beverages themselves pose hazards and opportunities. Even the sceptical and faintly absurd guidelines released by the American College of Medicine support an increase of urine volume as a stone prevention.
But the total urine volume we estimate from 24 hour urine collections hides a great danger.
First, a word about the graph. The bars display urine volume in milliliters per hour; 30 ml is a shot glass – one ounce. B, L, and S are breakfast, lunch, and supper; H is home. ON is overnight. Red is normal people. Green and blue are calcium oxalate and calcium phosphate kidney stone formers. The lines are standard errors.
Fluids by day sustain high and stable urine volumes. But overnight, while only the moon rages, volume falls to conserve water within the body. Our patients conserved even more efficiently than our normals.
Since supersaturations vary inversely with urine volume wise physicians and wise patients should best aim high. Push urine volumes as high as possible. And, perhaps, fear moonlight.
But unlike urine volume, kidney stone formers lose far more calcium in urine than normal people (red bars) do. They do this because of genetic – idiopathic – hypercalciuria (IH). Their higher urine calcium loss persists into the night.
As a consequence and not surprisingly, urine calcium concentrations (right panel) among patients exceed the normals. They differ most overnight.
Think about this. While our stone formers slept, they conserved water like normals, but lost far more calcium into their urine. Calcium concentrations peaked. Even their evenings were risky. In truth, patients throughout the day occupied the siege perilous, a place unsafe except for those somehow specially immune to crystal formation.
Like calcium, citrate excretion rises promptly with meals and stays up all day. But kidney stone formers and normals scarcely differ. So urine citrate concentrations fall by afternoon in both, just as, in patients, calcium concentration most rises.
At night, citrate concentration rises, but much less than calcium. For example, compare overnight calcium molarity of about 6 to citrate – less than 2. Because it’s overnight concentration so much exceeds that of citrate, much of the calcium is free to combine with oxalate or phosphate and form kidney stones.
A word about the graph. To avoid extra zeros, I graph the very small urine oxalate excretion rates and concentrations in umol/hour, millionths of a mole instead of the thousandths of a mole for calcium and citrate.
A long standing myth held that changes in oxalate concentration raised supersaturation more than equal changes in calcium concentration. Like all myths this one was easily proven false. So we can view oxalate excretion and concentration with the same cold eye as for calcium, and citrate.
Many have said that urine oxalate excretion by stone formers exceeds normal, but apart from a few scattered high blue bars (calcium phosphate kidney stone formers), our three groups excreted much the same amounts. Meals hardly influenced urine oxalate excretion, perhaps because the diet contained 1,200 mg of calcium.
The oxalate concentration pattern resembles that of calcium in having a nighttime peak. But steady urine oxalate excretion and rising urine volumes pushed oxalate concentration down in mid day.
The pattern of phosphate excretion matches neither oxalate or calcium or citrate. Excretion rises throughout the day then falls abruptly by night. As a result its high fasting concentration falls with feeding and attendant fluids, then rises progressively throughout the day into the night.
Need I say, like oxalate and calcium concentrations, high nocturnal of phosphate concentrations can promote kidney stone formation.
Just as during a few meal periods calcium phosphate kidney stone formers excreted more oxalate than others (blue bars in the prior figure), so did calcium oxalate kidney stone formers (green bars). To these small variations I attach little meaning.
As you might expect, the urine pH of the calcium phosphate kidney stone formers (blue) is higher than that of the calcium oxalate kidney stone formers (green) and in fact higher than that of urine from normal people, too. High pH raises calcium phosphate supersaturations because it increases the fraction of urine phosphate that can combine with calcium.
Overnight, calcium oxalate kidney stone formers have a very low pH, so calcium phosphate crystals cannot form. Calcium phosphate kidney stone formers have a much higher pH, so calcium phosphate crystals could form. pH of normal people lies between them.
Urine Uric Acid
Like most urine constituents, uric acid excretion rises with meals, but not as much as urine volume does so concentrations tend to fall during the day. Overnight, excretion falls.
Concentrations are much like those of oxalate with a distinct dip in the middle of the day and marked peaks overnight. There is little variation between the patient groups and between kidney stone formers and normal people.
Note, these are calcium kidney stone formers, so the uric acid excretions are not related to uric acid kidney stones.
Like minor comics prepare an audience for the star, like a concert orchestra plays something by itself to accustom the audience to listening before the grand virtuoso seats herself before the keyboard, all of the main components of supersaturations have had their hour upon the stage.
As you might expect, calcium oxalate supersaturation is rather constant all day, but high at night. By contrast, that for calcium phosphate rises all day long and peaks at night.
But the dashed line at 1 tells a different story. Normal people do not produce an average calcium phosphate supersaturation above 1 – the point where crystals can form – whereas both kinds of patients regularly do so. Calcium phosphate crystals form the bridge between plaque and nascent new stones. Likewise, calcium phosphate crystals plug terminal ducts that can anchor new stones. Need we wonder that calcium phosphate supersaturations best separate kidney stone formers from normal people?
Uric Acid Supersaturations
Being calcium kidney stone formers whose kidney stones contain no uric acid crystals, one should expect from our patients no significant supersaturation for uric acid above that found in normal people who of course produce no kidney stones at all.
In fact, our patients and normals hardly differ.
Uric acid kidney stone formers produce much lower urine pH values than these, and therefore higher supersaturations. But we have none to show from a controlled CRC environment.
Whether their daytime values dip I do not know.
The principal maxim holds: Urine supersaturations of active kidney stone formers are too high with respect to the crystals in stones forming. Lower them. But the graphs tell us 24 hour urines show us only averages of a volatile measurement whose peaks, by night especially, far exceed the overall day’s average.
So supersaturation management requires we respond to what we cannot directly observe.
Because we see less than what happens, underestimate the worst of things. To lower the average by half seems impressive. But overnight supersaturation may not fall at all if fluids stop after dinner.
Physicians, patients: consider this. Judge carefully. Be bold with fluids, exert all energies to lower urine calcium, and oxalate, and to raise urine citrate. Remember, always, the perils of the night.
How Do We Lower Calcium Supersaturation?
We alter urine volume, and excretions of calcium, oxalate, and citrate. These four greatly affect both calcium oxalate and calcium phosphate supersaturations and can be changed through diet and drugs. Likewise, in epidemiological studies, they link directly to risk of new stone formation.
How Risk Was Ascertained
In two female (red) and one male (blue) cohort followed over decades, some people began forming kidney stones whereas more did not. Using 24 hour urine samples from both, from each cohort, Gary Curhan could estimate the average relative risk of kidney stones shown here for all four urine excretions at the top of each bar. The bottom of each light bar marks the lower 95th percentile of that risk for calcium and oxalate, whereas the top of each light bar marks the upper 95th percentile for citrate and urine volume. Red bars help visualize the tops and bottoms.
In all three cohorts – the two female cohorts in red and the male cohort in blue risk rises with increasing urine calcium. The bottom of the bar rides above 1 for all three groups above 200 mg/day of urine calcium.
As urine oxalate rises kidney stone risk increases pari passu. If urine oxalate exceeds 25 mg/day one can lower it using high diet calcium and food oxalate precautions.
Citrate runs backward from calcium and oxalate – it is against kidney stones because it can bind calcium and inhibit calcium crystal formation. Therefore I have plotted the mean value downwards with the upper 95th percentile at the top. When that upper percentile it falls below 1 levels are high enough to reduce excess risk to 0.
Uniform high risk – red bars above 1 – begins only when urine citrate falls below 400 mg, in either sex. As for calcium and oxalate, one can raise urine citrate with reasonable rationale when below 400 mg/day using citrate supplements and increased potassium rich foods and beverages.
Just like citrate, higher volumes are protective so I have plotted the upper 95th percentile. Risk falls progressively as urine volume rises. Above about 2.25 liters daily the risk ratio is safely below 1. I have used this threshold in my analysis of how to prescribe fluids.
A Strategy for Clinical Supersaturation Management
Given the maxim, I act to lower supersaturations of active stone formers and aim for half or less of what I first find. I present the clinical complexities of such actions elsewhere. Of the main factors, I always try to alter all that raise risk using fluids and diet before drugs. Altering all creates synergies.
How Do We Lower Uric Acid Supersaturation?
I mean to say little for we need little: Raise urine pH above 6 and uric acid crystals will not form but may dissolve. No patient need form a recurrent uric acid stone. I favor potassium citrate over diet and beverages to assure stone prevention or growth.
How Many 24 hour Urine Collections?
How tempting to use one – cheap, convenient, and bespeaking of parsimony in medical practice. But I say shortsighted and wrong. One urine can mislead us, enough we miss the mark. One stone can cost ten or twenty urine studies, and as many days of pain and lost work.
We Compared Several Samples for Each of Many Patients
I measure 3 baseline 24 hour urines before beginning treatment. A single large practice collaborator
collected two such urines before treatment. We pooled the first vs. the second from the practice and the first vs. the third from my own practice asking how much variation is present between the first and subsequent collection.
Data from my practice (outlined by a solid ellipse) and from the collaborator (dashed ellipse) calculated to contain 68% of the data points overlap almost completely. Men are on top, women on the bottom.
One Collection Will Not Do
Although values from the two urines correlate with one another, values for any one patient can diverge by a lot.
To see this, simply draw or imagine a vertical line at 200 mg of calcium in the lower left panel of the figure. It intersects with the bottom of the ellipse at about 120 mg and with the top of the ellipse at about 300 mg/24 hour. The first urine could place a patient at no risk for kidney stones from urine calcium excretion, the second place the same person as high risk. Since the ellipse contains only 68% of the data, the actual spread can be much larger.
Others Have Found The Same But Concluded Differently
Because the ellipses are narrow and point upward and to the right at about 45 degrees, other scientists have made wrong recommendations. Charles Pak said that given the correlation a single urine is sufficient. Doctors Eisner and Stoller came to the same conclusion.
But they are wrong. Their own data show the very same individual variability as ours. One urine can misleads physicians and patients. I hope Drs Pak, Eisner, and Stoller do not resent my concluding other than they did, and invite their rebuttal and argument. But to me their data look much the same as mine, and we differ mainly in how to interpret it.
Supersaturation and Clinical Judgment
The maxim depends on a few details.
You must know stone crystal types.
You must determine if new stones are forming – if patients are actively producing stones.
Patients must provide 24 hour urine samples that reflect life as lived. They may know what they did but you must ascertain if what they did provides an honest representation of how they live their lives. Especially, do their samples represent how they lived their lives when they formed new stones.
How low to push supersaturation depends on how many peaks one thinks may hide within a mean, and how high? This depends on how much you know about their lives as lived, their work, their habits.
Clinical supersaturation means to use a quantitative and powerful measurement guided by what I can only call clinical judgment. We do not teach that in schools, it is patients teach us, and, perhaps, time.
Cautions and Reservations
In our clinical research unit, people drank as they chose but no doubt drank more fluently and perhaps more than usual during common life.
Although we found overnight and fasting volumes less than daytime, the world may produce other patterns. Someone doing orthopedic surgery, driving an 18 wheel Semi, teaching nursery school classes, or putting up house framing in the summer might have as low a urine volume by day as by night.
A clinical corollary: Ask your patient about work, driving, airplanes; tell your doctor about splitting 5 cords of wood for your winter fuel.
All this refers mainly to urine volume but even more happens out on the street. Not everyone eats three meals a day. Some people snack or starve until supper. Many vary so much from day to day no urine sample will be ‘representative’.
Take what I show as an idealized view of things. Work from there.