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The Basics of Cystine Stone Formation and Prevention
By Matthew LewisIn this tutorial we will look at the basics of solvent/solute relationships, how they apply to Cystinuria, and the general methods of preventing stone formation.
Table of Contents
Two Important Terms
Cystine Stones and Rock Candy: Understanding Solvents and Solutes
Tipping the Scales: Taking Control of the Cystine to Urine Ratio
The Saturation Point
Methods of Stone Prevention
What Have We Learned?
Two Important Terms:
Before reading this tutorial, it is important to have some knowledge of two main terms related to solutions. Understanding the terms solvent and solute, are key to understanding the problem of cystine stone formation. A solvent is a substance that will dissolve a solute. A solute is simply the substance being dissolved. Solvents are usually liquids, such as water. Solutes are usually solids, like sugar or table salt. By adding a solute to a solvent (adding sugar to water) you are dissolving that solute.
Cystine Stones and Rock Candy: Understanding Solvents and Solutes
The formation of cystine stones in individuals with cystinuria is promoted by the high concentration of cystine in the urine; the result of absent reabsorbtion by the kidney. Cystine stones are formed when this concentration exceeds the saturation level (the largest amount of solute that a specific solvent is able to dissolve at a given temperature) and the excess precipitates out of solution as individual crystals, which then aggregate to form stones.
If you have ever made your own rock candy as a child, you have already experienced this phenomena first hand. In order to make the rock candy, a given amount of water is brought to a boil (which simply raises the water's saturation level, allowing it to hold more solute in solution) and sugar is added to it. The amount of sugar added should be just below the saturation level of the boiling water, meaning that it will all go into solution but any more would lie as a solid on the bottom. Then the whole mess, which should be the consistency of syrup, is transferred to a drinking glass, and a string attached to a pencil lying across the glass's top should be dangled down into the center of the solution. As the solution cools down, the water's saturation level drops back to that of normal room temperature water, and its ability to hold the sugar decreases. As a result, the dissolved sugar begins to come out of solution in the form of solid sugar crystals. Some of these crystals fall to the bottom of the glass and some might stick to the side, but many stick to the rough surface of the string. Once a few sugar crystals are in place on the string, the string is “seeded”. Over the next few hours or days, as water evaporates and more sugar is forced out of solution, the crystals easily attach to the existing crystals on the string. (Once a single crystal has “seeded” an object, other crystals will find it more favorable to compound upon that crystal than to attach themselves at other points along the object) The resulting aggregate of sugar crystals is the rock candy: pure sugar that has an overall shape roughly defined by the shape of the tiny sugar crystals that compose it.
Cystine stones are formed in much the same way. Due to the lack of reabsorbtion of cystine and other amino acids caused by cystinuria, those affected amino acids will remain in the urine in higher concentrations than that of an unaffected person. Those concentrations will build up until their respective urinary saturation points have been reached, and then the excess will not be allowed to go into solution. The result is the adhesion of individual cystine crystals (acting like the sugar in our example) to other cystine crystals, (acting like the string). More cystine crystals then find it favorable to compound upon the existing crystals, and thus the stone “grows”. At some point, the stone may dislodge from its place of growth and begin its long painful journey through the urinary tract. More solid cystine crystals are forced out of solution, anchor themselves to each other, and the process repeats.
Tipping the Scales: Taking Control of the Cystine to Urine Ratio
We now know that stone occurrence is dependent on a solute/solvent relationship, and the value of this relationship (the ratio of cystine to urine) will influence the rate of stone formation. For example, if the amount of solute (cystine) is very low and the volume of solvent (urine) is very high, the few cystine crystals will be able to dissolve completely in the abundant urine. If the amounts are reversed with the solute very high and solvent very low, the result should be a large solid block of cystine with too small an amount of urine to dissolve any significant portion of it. A person with normally functioning cystine transport in their kidneys will tend to lean toward the 1st extreme. A person with cystinuria will lean more towards the 2nd. However, any person can manipulate his or her own ratio to achieve one outcome or the other (to a limited practical extent).
The Saturation Point
Half way between these two extremes, we find a mid-way point: the ratio of solute to solvent at which stones neither form nor dissolve . At this exact concentration, the amount of cystine going into solution (being dissolved) is exactly equal to the amount coming out of solution (precipitating) at any given time. On either side of this mid-way point, the outcome will begin to look like that of its respective extreme. Although researchers have made numerical measurements of this midway point (the most accepted being 250 to 300 mg cystine per liter volume at pH 7.0), the exact number value is not immediately important. For now, don't think of it as a number. Rather, think of it as simply a dividing line that separates two very different results.
This “line”, by definition, is the saturation point of cystine in urine at normal physiological conditions. (Some of these conditions that would affect the saturation point such as body temperature and urine pH will vary very slightly from person to person, therefore this saturation level is an approximate value.) This makes sense, because previously we learned that any amount of solute added past the saturation point would remain solid. In the case of cystinuria, any cystine present above the saturation point will remain as solid crystals and can potentially form stones. Knowing this, the real question that should be on the mind of every cystinuric is: "Since this solute/solvent ratio can be manipulated, how do I swing mine so that it lies below this mid-way point?" In other words, "How do I lower my cystine to solvent ratio so that the cystine concentration present does not exceed the saturation point?" Those questions lie at the crux of stone prevention.
Methods of Stone Prevention
The goal of dietary and medicinal changes for the sake of preventing stones, as stated, is to lower the ratio of cystine to urine, ideally below the saturation point. This can be accomplished by following any of three main treatment pathways. The first option is to lower the amount of solute (cystine) that ends up in the urine. The second is to increase the amount of solvent (urine) present. The third less obvious method is to increase the solubility of the cystine in the urine, either by modifying the cystine or the urine, essentially pushing the previously mentioned saturation point higher. Of course, a combination of these three is most effective. It should also be noted that some of the prevention methods included in these three main groups have the potential to reverse cystine stone growth as well as prevent it, although each is generally far less efficient at reversal than prevention. Let's look at these three main paths of prevention, and then link to a detailed review of the individual methods and medicines.
1) Lowering the amount of solute (cystine) in the urine:
Swaying the solute to solvent ratio by lowering the amount of cystine in the urine can be achieved through dietary modification. To have less cystine in the urine, you must have less of it in your body to be filtered by your kidneys (with one important exception, discussed in the following paragraph). Cystine, as described in the amino acid tutorial , is a molecule composed of two cysteine amino acids (note the extra "e") joined by their sulfur atoms. Being a non-essential amino acid , it is synthesized in the body from another amino acid, methionine. Methionine is not a non-essential amino acid (rather, it is an essential amino acid ), meaning it must be consumed to enter the body; the body can not synthesize it. As a result, cysteine (and thus cystine) enters the body only via the ingestion of either cysteine itself, or the ingestion and "breakdown" of methionine. Since both are amino acids, it is more simply the ingestion of protein that allows cysteine to enter the body. Therefore, to lower the amount of cystine in the urine, a person should theoretically be able to limit their protein intake. Furthermore, some protein sources are considered to be higher in methionine and cysteine content, such as fish. Eating less protein that is rich with these amino acids should theoretically help reduce the amount of cysteine entering the body.
There is one important known exception to the above rule, and it too falls under title of "dietary modification". Lowering the dietary intake of sodium (most commonly from table salt and processed foods) has also been shown to reduce the amount of urinary cysteine. This works because sodium can cause cystine to be drawn from the body, where it is harmless, into the urinary system where it can form stones.
2) Increasing the amount of solvent (urine):
Swaying the solute to solvent ratio by increasing the amount of urine present to dissolve the cystine can again be achieved through dietary modification. The only way to increase the amount of urine, (with the exception of using diuretics, discussed in the following paragraph) is simply to ingest more fluid. In theory, any amount of cystine excretion can be controlled with the appropriate ingestion of fluids. For example, if a person's cystine excretion in one day is twice what it was the previous day, that person can drink double the amount of water and end up at the same cystine to urine ratio. Just remember that what you excrete is always less that what you consume since some is always "lost" to the body, so if you're shooting for a 3L/day urine output, you should be drinking 4 or more liters. In practice, a daily consumption of anything above 4 or 5 liters may becomes difficult to maintain.
Again, there is an exception to this general rule. Some foods and fluids (as well as drugs) will cause a higher than typical percentage of liquid volume to be released to the kidneys. These are called "diuretics", and they function to increase the amount of urinary output volume. Beer, coffee, and soda are common diuretics (generally anything containing alcohol or caffeine). These substances, when used in moderation, can be helpful to a cystinuric person (eg. in the event of stone passing), as long as care is taken to replace the excess lost fluid. Without continuous replacement of the lost fluid, the use of diuretics is not a sustainable method for increasing urine output.
3) Increasing the solubility of cystine in the urine:
Making a given amount of cystine dissolve more easily in a given amount of urine requires chemical alteration of either the cystine or the urine. Chemical alteration of the cystine is accomplished by drugs containing chemical compounds that break apart cystine molecules and attach themselves to the individual cysteines, making a complex that is more soluble than the original cystine. Chemical alteration of the urine is accomplished by alkalizing agents that raise the pH of the urine. Since cystine becomes significantly more soluble as pH increases, these agents can be effective at allowing large amounts of cystine to be dissolved in a given amount of liquid.
What Have We Learned?
To recap, we have looked at the basics of why and how stone prevention works by boiling the issue down to its fundamental core: the solute to solvent ratio and the saturation point. We have learned about the three general methods of favorably manipulating that ratio and saturation point for the purpose of prevention (and treatment, to a limited extent), and understand the basis of how each contributes to the overall goal.
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