Supersaturations Guide Fluid Prescription
A patient, a physician, both can write down fluid goals. But how do we know the right amount? How do we write the proper fluid prescription for kidney stones?
Indifferently, kidneys supersaturate urine whenever driven to conserve water. With the same indifference, they dilute the urine if confronted with extra water they must eliminate. But we cannot share their indifference. If more fluids protect against stones, frequent voidings disturb our lives and our sleep.
Clearly, the ideal fluid prescription lies between the Scylla of urine supersaturation and the Charybdis of excessive voiding.
How do we navigate between them?
How do we write the right fluid prescription?
Kidneys Supersaturate Urine By Doing Work
They Filter Lots of Water From Blood and Reabsorb Almost All of it.
Kidneys use the work of the heart to filter a large amount of water out of the blood every day: About 140 liters, or 36.98 gallons.
People in general produce about 1 – 2 liters of urine a day, or 0.26 to 0.52 gallons. So kidneys concentrate the filtrate by 70 to 140 fold. This process of removing the water from the filtrate back into the blood requires energy and does work on the solution. It is identical to the evaporation experiments we have already spoken of elsewhere. Such work produces supersaturation.
Kidneys Filter Salts Out of Blood and Reabsorb Variable Amounts
Some molecules that produce stones, like oxalate, play no useful role in the body and need to be removed. The amount removed depends on how much is produced in the body and absorbed from foods. Others like calcium and phosphate and citrate are conserved by complex biologies as well as by how much is absorbed from foods. Regulated transporters control urine acidity or alkalinity, measured by urine pH; work done on urine to change pH can raise supersaturation.
Stone formers tend as a group to conserve calcium less and citrate more than normal, so for any amount of water the amount of calcium is higher and citrate lower than in normal people. Because citrate binds calcium and inhibits calcium crystal formation the high calcium to citrate ratio in urine of stone formers synergizes with water conservation to raise supersaturation.
Supersaturation Reflects the Proportion Between Reabsorption of Water and Salts
Crudely and incompletely put – there is a lot of complexity here! – people make kidney stones in part because of an imbalance between urine losses of calcium, oxalate, citrate and water. Whether this imbalance arises from genetics, habits, vocation, systemic disease, or chance, it can produce or increase supersaturation.
What We Drink Controls Urine Supersaturation
So far as we know, kidneys pay no heed to urine supersaturation. To prevent dilution of blood sodium they rapidly remove extra water we drink. If we do not drink, they conserve water to protect blood sodium concentration. So we can regulate our own urine volumes by how much we drink. We determine if our kidneys supersaturate urine more, or less, or perhaps even not at all.
Which Supersaturations Matter?
The ones that relate to the crystals in stones formed.
Stone analyses disclose those crystals. Urine supersaturation drove those crystals to form.
Given the common calcium oxalate kidney stones, both calcium oxalate and calcium phosphate supersaturations matter because calcium oxalate grows over an anchor of calcium phosphate on the inner surfaces of renal papillae. Sometimes, calcium oxalate kidney stones form on the ends of calcium phosphate plugs in the terminal portions of the kidney’s tubules – where the final urine leaves the kidneys. Either way, some calcium phosphate crystals must form that calcium oxalate can anchor on.
For calcium phosphate kidney stones, calcium phosphate supersaturation matters most. Sometimes stones contain both crystals, and both supersaturations may matter.
Given this logic, calcium phosphate supersaturation always matters.
For uric acid or cystine stones, those supersaturations most matter.
What We Cannot Consider Here
Here we consider only the two calcium stones, leaving uric acid and cystine for another time. Likewise, we restrict ourselves to stone formers without a systemic disease as a cause of stones. Systemic diseases pose their own special problems.
Some patients who form stones have diseases that do not cause stones but reduce the safety of high fluids. Heart failure, chronic kidney or liver disease, malignant tumors all may limit fluids. Likewise medications such as diuretics, psychoactive drugs, and more may matter. Only physicians can manage these complexities.
Fluid Prescription Varies Over the Day
The Big Picture
The featured image at the top of the post tells the story for calcium oxalate and calcium phosphate.
It shows urine supersaturations along the vertical axes as ratios. Values for calcium oxalate lie on the top row, those for calcium phosphate on the lower row. At the solubility point (dashed horizontal line at 1) crystals neither form nor grow. Below 1 (undersaturated) more could dissolve. Above 1, supersaturation, crystals can form and grow.
The urine flow rate runs horizontally along the bottom axis. It’s units are milliliters per hour; 1000 milliliters make up a standard 1 liter water bottle. A liter is 33.8 ounces, just slightly more than a quart (32 ounces). So 100 milliliters (where we put the dashed upright line) would be 1/10 liter, or about 3.4 ounces per hour of urine flow. That would be 2.4 liters (or quarts) a day.
What Are Our Supersaturation Goals?
Obviously, supersaturation falls as urine volume goes up. We expect that. But how low, and why?
We Have No Trials
Because of crystal modulating molecules in urine and the complexity of how crystals actually form no supersaturation must be ‘safe’ except if below 1. We can hardly ever lower calcium oxalate supersaturation that low, and only sometimes do so for calcium phosphate. So we need some usable principle or maxim, and articulated one in another article.
The Principle or Maxim
If new stones are forming, supersaturations of urine samples obtained under conditions that reflect everyday life are too high in relation to crystals in stones forming. Dr. John Asplin offers lowering it by half. Crudely put, this makes an average goal around 4 or 5 or less for calcium oxalate, and about 1 or less for calcium phosphate, given the average levels of supersaturation observed before treatment.
Fluid Prescription Over the Day
The left panels of the featured image show kidney stone formers (red) and normal people (blue) before breakfast, which means fasting since the night before.
Almost all the urine samples are supersaturated with respect to calcium oxalate (upper panel; most of the points are above the horizontal dashed line at 1). Below 100 ml/hr (3.4 ounces/hour) supersaturations rise steeply.
By contrast, many of the urines are undersaturated (below the dashed line at 1) with respect to calcium phosphate (lower left panel). Even so, below 100 ml/minute, the percentage rises steeply.
Stone formers (red points) have higher supersaturations than normal people (blue points) for the reasons we already mentioned: They tend to lose more calcium, or oxalate, or less citrate in their urines than normal people, so for any amount of urine their supersaturations are higher.
The fluid prescription: Keep urine flow above 3.4 ounces an hour between arising and breakfast.
As noted in the review of the Pak experiment (below), the difference between 24 hour urine volume and actual fluid intake is about 0.9 liters (900 milliliters), or 37.5 milliliters (1.1 ounces) per hour. Rounding, to avoid confusion, we need 3 – 4 ounces of urine or 4 – 5 ounces of fluids an hour.
Urine calcium losses, especially, but also losses of oxalate rise more with meals in stone formers than in normal people, which creates a need for even more water than is needed while fasting. The middle panels show the consequences. It takes roughly 125 ml/hour (4.25 ounces/hour) to keep supersaturations below 1 for calcium phosphate and below 5 or so for calcium oxalate. Given the extrarenal water losses mentioned above of about an ounce an hour, this comes to 4.25 + 1 ounces an hour, or about 5.25 ounces an hour.
Fortunately we tend to drink while eating. The graphs make clear that lots of people were drinking even 10 ounces of fluids per hour.
Like the other periods, urine flows below 100 ml/hr (3.4 ounces/hour) produce a steep rise of supersaturations (right upper and lower panels). Although urine calcium losses fall over night, they do so less in patients than in normal people. So we need about 5 ounces per hour.
The Grand Total Fluid Prescription
People all live their own lives and many, perhaps most, deviate from the food schedule we used for this research. So we can total up all the fluids needed in our study as an example, but expect people will modify it to their needs.
Given fasting of 2 hours, at 5 ounces an hour (10.5 ounces (0.3 liter) total), fed of 14 hours from first meal to bedtime, we need 14 * 5.25 = 73 ounces (2.1 liters) total.
Overnight, 8 hours, at 5 ounces an hour, 40 ounces (1.2 liters) total.
Altogether this makes 123 ounces (3.6 liters) of fluid intake a day in this example. One can calculate for the fasting, fed, and overnight periods of a patient to obtain a more refined estimate.
Urine Volume Effects In 24 Hour Urines
Up to now our data have come from subjects all eating the same foods in a clinical research unit. What about the street? How do things look if we use just 24 hour urines collected with no control of anything – diet, fluids, behavior? From our own clinic and from many practices that used Litholink in its early days, we collected 24 hour urine samples that answer the question.
How We Plotted the Results
For the left hand panels, we divided urine calcium into quartiles (mg/d): <144 (green), 145-216 (red), 216-301 (blue) and >301 (black) and plotted SS on a log scale to accommodate the wide range of values. We overplotted simple linear regression lines on the four separate color bands to show slopes.
Just as for hourly collections in the Clinical Research Center, and despite no control of diet, SS for CaOx varies strongly with urine volume (upper left panel). CaP SS lower left panel) correlated less well because more dependent on urine pH.
Effects of Urine Calcium
SS for CaOx and CaP varied with the quartile of urine calcium enough that the four color bands separate visually despite some overlap. The lowest quartile fits well with average urine calcium of normal people. The blue and black quartiles represent urine calcium levels associated with increased risk of kidney stones.
The four ascending urine calcium quartiles form a set of ascending ramps, so at any one volume SS rises as you climb up from one ramp to the next.
Effects of Urine Oxalate
We divided urine oxalate excretion into tertiles that roughly spanned the main stone risk regions derived by Curhan: <25, 25 – 40 and >40 mg/d. Calcium oxalate supersaturation rose markedly with rising urine oxalate quartile (upper right panel), as expected. We do not show effects of urine oxalate on CaP supersaturation because it should be and in fact is irrelevant – no effect.
Effects of Urine pH on CaP Supersaturation
Instead, we plotted CaP supersaturation against urine volume, in the lower right panel, and graphed it by four levels of urine pH: <5.5, 5.5-6.5, 6.5-7.5, and >7.5. At the lowest pH, in green almost no urine volume is low enough to create a supersaturation above 1. When pH rises above 7.5, supersaturation exceeds 1 no matter how high the urine volume. So the regression line is horizontal.
Although the lines for the four quartiles have different slopes, one gets about 50% lowering for a one liter increase of volume for the two middle quartiles.
The urine volume our fluid prescription should produce, about 2.5 liters daily, should lower CaP SS below 1 for most patients in the lower three calcium quartiles. Likewise it will lower CaOx SS below 5 in the two lower calcium quartiles Given corrections for insensible losses this comes to about 3 liters of fluid intake, a result much like we got from the clinical research unit data.
But our data offer a warning. When urine pH is high, CaP supersaturation will not yield to volume. More must be done.
Urine Calcium Effects In 24 Hour Urines
Urine calcium exerts a powerful effect on stone risk in the Curhan data. It also raises both CaOx and CaP supersaturations as was obvious from the prior graph. But what about urine citrate, and urine pH once calcium is itself accounted for?
When supersaturations for CaOx and CaP are plotted against urine calcium the three grades of urine citrate we derived from the Curhan data (mg/d) <400, 400 – 600 and >600 had almost no effect; the three regression lines hardly separate.
We are surprised a bit in that calcium binding by citrate might have been expected to alter supersaturations more than this. Probably what the graphs really suggest is that urine citrate works mainly by affecting crystal formation, not simply via supersaturation reduction.
Over same quartiles we used in the prior graph just above this one, urine CaOx SS fell remarkably as pH reached the top two – >6.5 in blue and >7.5 for the black line. This is shown in the lower left hand panel. As expected from what we already showed you in the volume plots, CaP supersaturation is almost unaffected by urine calcium excretion and fixed above 1 at the highest urine pH – black line, and almost always below 1 at the lowest pH – green line.
Value of Multiple Treatment Modalities
These data, from all sources, show why multiple treatment modalities work better than dependence upon only one. For example, lower diet sodium can lower urine calcium so a patient moves from a higher to a lower calcium quartile and therefore a lower urine SS at any given urine volume. More urine citrate or less urine oxalate excretion will do the same. Changing urine pH or urine oxalate, will also matter.
We did not produce all possible plots but high calcium diet that lowered urine oxalate would equally create a range of bands like those for calcium, and the same for changes in urine citrate.
A Direct Experiment
In 1980 Pak and Sakhaee varied urine volume in people and measured resulting saturations. They also related fluid intake to the resulting urine volume. This gave the 0.9 ;/day correction we used in our fluid prescription calculations.
What They Found
They incubated samples of urine with an excess of the solid phases – calcium oxalate, and calcium phosphate in the form of brushite – so as to bring the sample to the solubility point. The ratio of the product of the calcium and oxalate ion activities (calcium oxalate) or calcium and hydrogen phosphate activities (brushite) before to that after the incubation is supersaturation.
They called this ratio the activity product ratio, or APR. EQUIL calculates the ratio of the salt (CaOx or CaP) in urine to its solubility and correlates directly with the APR but a plot of our SS against APR has a slope greater than one. So at solubility both would be 1, but as APR rose the SS we calculate would rise faster.
Effects on Saturation
As they increased urine volume in their subjects (left panel of their figure), supersaturation fell for CaOx and brushite. We do not consider sodium hydrogen urate here, and ignore those points.
At about 2.5 liters, that for calcium phosphate (Br) fell to solubility (the line at 1) and that for calcium oxalate (CaOx) to about 2. The stars give estimates of the significance of the fall. Our average calculated SS for CaOx were about 5 at that volume. GIven the scaling differences between APR and EQUIL SS, this would be about a value of 5 as we found. For CaP, like them, we found most values below 1 (see the previous figure).
Our detailed review of supersaturation presents three zones: undersaturated; metastable supersaturation – like most urine; and unstable supersaturation – where crystals are forming and the energy of the solution is running down. The formation product ratio is the activity product ratio (their estimate of supersaturation) at which the urines they studied enter the unstable zone.
For calcium phosphate that zone is about 4 – 5 and is unaffected by volume. For calcium oxalate it is a lot higher, and rises with water. So the protective effect of diluting the urine seems greater for calcium oxalate: the floor – saturation – goes down while the ceiling – formation product – goes up.
Their formation products are the Ostwald limits written about elsewhere.
How Much Do We Drink?
They found that 1.8 liters of intake gave 1.02 liters of urine; 2.3 liters gave 1.35 liters of urine; 2.8 liters gave 1.88 liters of urine and 3.3 liters gave 2.38 liters of urine, Differences between intake and urine of 0.78, 0.95, 0.92, and 0.92 liters/day. This means that to get the highest protection they observed, we would need 3.3 liters (112 ounces) of fluid a day, a value close to that from our CRC and 24 hour data.
The Fluid Prescription for Kidney Stones
A Standard Estimate
Because we have no trials, we cannot say that calculations based on our data will yield better results than just an overall 24 hour goal of above 2.25 liters that Curhan found at the threshold of kidney stone risk. But there seems no risk to doing the simple arithmetic: 100 ml/hour fasting and overnight, 125 ml.hour from breakfast to bedtime. This would be a kind of standard estimate which can be varied depending on the circumstances. Overall, this value would be about 3 – 3.5 liters daily.
Alternative Estimates of Supersaturation Goals
We have already pointed out that because of the many crystallization modifying proteins in urine one cannot say a particular supersaturation is ‘low enough’ in general. Many normal people have high urine supersaturations as in the 24 hour urine and featured graph, but do not form stones. Very many stone formers have urine supersaturations that overlap with those of normal people.
Activity of Stone Formation
For this reason, we have proposed on this site that the supersaturation of an active stone former is too high. Active means that new stones are forming as opposed to passage of stones what were present in the kidneys in the past. A reasonable goal is to lower the supersaturation by half regardless of its absolute value.
Using this criterion, many people on our graphs would need more fluids. For example, those with supersaturations of less than 10 for calcium oxalate who were actively forming stones would have to lower that supersaturation well below 5. This could require more fluids than in our standard estimate.
Other Treatments Beside Fluids
Throughout we have calculated as though we lowered supersaturation only by increasing urine volume. But of course we use other treatments that may reduce the need for fluids.
Such treatments lower urine calcium or oxalate, or raise urine citrate.
Even so, because fluids safely reverse the renal process that supersaturates urine, they have about them as a treatment what we might call elegance – a simple and effective means of accomplishing a goal.
The value of 0.9 liters for daily non-renal fluid losses does not apply everywhere. People live in deserts. Some build buildings outdoors in summertime, work in kitchens or in foundries. Think about workout enthusiasts, professional athletes. All of these people need more fluids than we calculate. Even the seasons matter, and sex, too. Men lower their urine volumes and raise supersaturations greatly in summer time, women do not.
HOW TO USE OUR OTHER POSTS ON FLUIDS
We have offered several posts on tricks for drinking more fluids, and how to make good choices of beverages. The goal volumes for these posts exceed those offered here. We made them generous just because many people may need very high fluid intakes. Consider them recipes for a large party one can scale back as needed.