Chapter One: Kidney Stones in General

As it should, Chapter one: kidney stones in general begins with the stones themselves. They cause the miseries and dangers of this disease. What causes them, genetic traits, habits, systemic diseases, they, too, can harm and I will come to them.

But the stones come first. They pose the immediate risks of pain, obstruction, infection, bleeding, surgical procedures, and all of the chaos and disruption of life those entail.

The featured image shows salt harvesting from evaporation ponds. Saltwater evaporates in sunlight, overload with sodium chloride that crystallizes out of solution, and workers collect the salt to sell for seasoning our food.

This chapter, like all that follow, rest upon the articles that carry much of the detail. I head major sections with links to the parent articles but suggest reading this text through. 

What Kidney Stones Are

Geological artifacts of crystallizations from a fluid overloaded with salts – that is a way to think about them. Like such artifacts one expects some randomness and chaos. Also we expect the internal organization of laminated rocks and pebbles that have sedimented out of streams or oceans over time. Even more, stones form in kidneys. So we expect something like in shells or even the shining mysterious pearl coated over with complex secretions layered over a disturbing grain of sand. We expect an imprint of the organ.

Stones are Crystallizations

Crystallizations – a key word. Salts crystallize out of solutions within the kidneys or the urinary system – urine; the fluid inside the tubules of the kidneys; perhaps the fluid inside the kidney tissue itself that slides between vessels and tubules. Nothing differs between this process and salt harvesting from ponds. Nothing. The ponds have a square shape so the salt cakes in squares. Kidneys and urinary systems have rounder complex shapes that stones wear as badges of their origins. Evaporative salt harvesting is not a metaphor for kidney stone formation. Rather it physically models stone formation, illustrates it in a simplified – because not biological – physical system. But essentially both are one thing.

Crystallization is a General Phenomenon

How can I say this?

Crystallization makes evaporative salt harvesting and kidney stones one thing.

For all crystallization arises from physical forces between atoms and molecules that follow the same laws everywhere. True, many molecules in urine – and maybe in ponds – can influence crystallization. Likewise, sodium chloride is not a kidney stone crystal. But physical laws that apply everywhere govern solid phase formation from dissolved ions and molecules. So salt ponds and kidneys share at least one thing in common.

Supersaturation Means Solutions Overloaded with Salts or Molecules

This word dominates kidney stone disease. It embodies the idea of ‘overloaded’ in a physically exact number that specifies the degree of overloading. Salt harvesting, kidney stones, any formation of solid phases from solutions requires supersaturation to drive that formation. The sun supersaturates the ponds by evaporating water. Kidneys supersaturate urine and fluid in its tubules by conserving water.

What Supports the Science of Supersaturation?

The sequence from salt harvesting to kidney stones to the general idea of supersaturation arises from borrowing. A century of physical chemistry research has established ways of quantifying crystallization. We can use this generational richness without establishing that what we have inherited is true in our special world of kidney stones.

Supersaturation lets us speak of and quantify crucial aspects of this human disease in physical chemical terms. In gives physicians quantitative measurements to track stone forming potential and its changes with treatment. If what we know resembles a mountain peak just above a vast deep sea, the waters around us are clear as crystal. We can see to the very bedrock causes of stones.

Supersaturation gives even more. It is a form of energy work can produce in solutions. So much like the roots of mountains, supersaturation links stone disease with thermodynamics.

Water as Treatment

The Hypothesis

Like pearl and shell they form, perhaps, but we set out to stop them, to prevent them. This requires we prevent the stone crystals. Since crystals come from supersaturation and kidneys supersaturate urine by conserving water, need we more than excess water? Will that not shut down their very engine?

Here we have a real hypothesis and its test. But how best to state it?

The hypothesis cannot concern whether crystallization requires supersaturation. That rests on undeniable physical ground. But the many urine molecules that affect crystallization could affect the level of supersaturation needed to create crystals. Perhaps people who form stones form crystals at supersaturations that other people tolerate without any crystal formation. Perhaps these molecules or even kidney cell surfaces promote crystal formation so well that supersaturations need be vanishingly slight.

How, then, can we best frame the hypothesis that would lead to a trial of water as treatment?

Here is my best on this: Within the range attainable in people simply drinking differing amounts of water mainly supersaturation determines if crystals and therefore stones will.

The Deduction

If this were true than enough water to raise urine volume to the maximum practical in everyday life should reduce new stones compared to urine volumes near the minimum encountered in everyday life. Should this prediction fail, supersaturation may not be an important factor in human urine or kidney crystallizations over the ranges achievable by fluids alone. That does not mean supersaturation has lost its physical meaning. But the complex molecular environment might so alter crystallization that effects of supersaturation become manifest at only extremes of fluid intake.

The Test

Crystals Must Be Defined

The very test narrows the hypothesis. Many crystals can make stones and some are poor candidates for the test. One kind, struvite, arises from the work of bacteria. Water will not stop it. Another is uric acid whose crystals form when urine is acid and dissolve when it is alkaline. More urine volume would help prevent them but prior knowledge makes the issue silly. Alkali cures them and concentration of urine plays a modest role as best. The relatively rare people with genetic cystinuria make cystine stones. The volume of urine needed to dissolve that amino acid far exceed what other stone crystals would need.The remaining stones all contain calcium oxalate and calcium phosphate in various proportions. Water could indeed reduce their formation as they depend strongly on kidney water conservation.

Patients Must Be Defined

But who will serve as a control – those not given large amounts of water?

The trial would require some candidates be allocated at random to no treatment, others to high fluid intakes. Could one ask patients who had formed – let us say – 30 stones to forego any treatment for 5 years?

How about 15 stones?

Would you ask even someone with 7 stones to forego treatment?

The one group possible formed only one stone. Not proven to recur, they often receive little or no treatment.

So, the trial enrolled patients who had formed only one calcium stone. Perhaps because the most common, all had formed calcium oxalate stones. But the stone analysis used chemical means not infrared spectroscopy, so to a modern eye seem questionable. Because stones in kidneys would mean more than one, they excluded all who had them. High blood pressure employs low sodium diet and thiazide drugs that also reduce stones, so blood pressures need be normal.

The Result

Ninety nine people who formed one calcium oxalate stone and drank so much they produced 2.6 liters a day of urine formed 12 new stones in five years. A hundred more just like them who produced only 1 liter of urine daily formed 27 stones in the same time. As expected water reduced supersaturations. So, the prediction from the hypothesis was not falsified. Supersaturation affects crystal and stone formation within the range attainable in people simply drinking differing amounts of water. In fact, calcium phosphate supersaturation was abolished, leaving some room for further experiments to estimate the range more precisely.

In passing the authors note that before the trial, at baseline, patients had lower urine volumes than their non stone forming subjects. One might surmise from this that habitual low urine volume played a role in causing their stones. But that is observation, not hypothesis testing.

Water as Less than Enough

Too Many Stones Despite Marked Hydration

Surely water works. But why so many stones? One hundred random people will not make 12 stones in five years drinking so much water as to achieve a urine volume of 2.6 liters daily. This would be 2.4 percent per year or 24 percent per decade. Even if limited to adult years this would produce stone rates approaching 75 percent in a population of high fluid drinkers.

For the controls, the numbers essentially double.

More is wrong than water could right.

Multiple Stone Formers Are Even Worse

In the parent article to this section, we show that people who have formed multiple stone form many more when treated than 12 in five years. This despite more water and medications. For example, more than half of the control groups in these trials formed new stones in only 3 years despite increased urine flow.

Why they do this may be accumulations of tubule plugs or plaque – the anchoring sites for stones to grow on, or perhaps whose who form many stones have more wrong, with their kidneys or urine.

But multiple or single stones, either way, something more must be wrong with people who form stones than simple habit. One clue to what might be wrong is in Table 4 of the original article that can be reached through the parent article to this one. Baseline, before anything was done, the urine calcium levels of those destined to relapse was higher than those who did not 233 vs.336 mg/d and 249 vs. 313 in the high fluid and low fluid groups, respectively; p<0.001 for those into statistics.

One Point for my Metaphor

The one about looms and all. No doubt low flow habits can promote stones – the free will part, the shuttlecock. But the numbers suggest that things are not always made right for a stone free low fluid life. Some people need more fluids than others. Maybe it is the higher urine calcium – high urine calcium would certainly promote calcium stones. Maybe more is involved.

Need for a New Hypothesis

Here, lies an example of how science works. People who have formed one stone mark themselves out as susceptible and not fully cured with water alone. Something makes them susceptible to stones. Is that something the high urine calcium, or something else?

Only imagination informed by the details of the study and of the whole field of kidney stone disease, only that imagination can envision something worth the trouble of testing. Nature offers an instance of opportunity. No doubt someone will dream, one day, deduce a test of the dream, and do the test.

What Science Tells Physicians

Water is a fine remedy for people with only one calcium oxalate stone, but not sufficient for the long term. Even if they maintain a very high urine volume of above 2.5 liters daily 12% will relapse by five years. Better to evaluate such patients and treat them with the full panoply of reduced diet sodium, increased diet calcium, reduced diet sugar as well as high fluids. That is, after all, the proper diet for all people, so why not for stone formers?

For those with many stones do not prescribe only fluids – evaluate and treat more fully.

Fluid Prescription for Kidney Stones

Even if fluids are not all one should do, we needed to fix some reasonable volume goals and did this by triangulation.

As always, I favor the work of Gary Curhan who showed that risk of new stones falls below significance above about 2.25 liters per day of urine flow rate. Because I believe urine volume affects crystallization via supersaturation, we inspected the response of supersaturation to increasing urine volume in large numbers of urine samples looking for a sweet spot. We found one at about 2.5 liters of urine daily. Above this point you get a diminishing fall in supersaturation for a given increase of urine volume. The one water trial achieved 2.6 liters of urine daily.

From all three we get a range of 2.25 to 2.6 liters of urine daily as reasonable.

The amount of fluids we need to achieve such volumes depends on where we live and what we do. At baseline we appear to lose about 0.9 liters daily elsewhere than our kidneys – breathing, sweating. So this gives a fluid goal of about 3.1 to 3.5 liters if fluids are the mainstay of prevention.

But if supersaturation is indeed what mediates between urine volume and crystallization, urine calcium, oxalate, and pH all seem modifiers of volume’s effects. Likewise if crystal inhibition by citrate matters, a rise in urine citrate might offset need for as much fluids. So in principle should one lower urine calcium and oxalate and raise urine citrate less volume might do. Trials can help here. But in general those that have modified urine calcium, oxalate and citrate also have increased urine volume more or less to above 2 liters. None have tried effects of lower volumes.

Crystal Specific Treatment

A Broad Brush

Water alone cannot do for even single stone formers. And high fluid intakes themselves can interfere with normal life enough people abandon them over time.

So, for most, treatment of even calcium oxalate stones must aim at more than water conservation. Such an aim requires we know the crystals from stone analysis, and know what else about the urine beside volume causes them to form. It also means we know more about what kidneys do, and how to alter what they do in favor of our patients.

Finally, this line of reasoning leads to understand that uric acid or struvite stones need their own specific treatment, as does cystinuria. And these treatments may differ a lot from those for calcium stones.

This places stone analysis at the first position for kidney stone prevention.

A More Rigorous Argument About Calcium Stones

Perhaps I have been glib, too hasty, and my logic requires a more stately pace.

For calcium oxalate stones, water succeeded and failed at the same time. I would be silly to deny water a place at the great table of therapies. But as much a fool as to leave no other open chairs. For even single stone formers we need more – perhaps for those with higher urine calcium losses. For those with many stones, the larger trials I only alluded to make clear water alone is insufficient.

High fluid intake reduces kidney the water conservation that overloads urine with salts. So water is a general overarching treatment. No other treatments are so general.

Therefore we need to consider specific treatments in terms of the what promote them, and what can be done to reduce their formation.

Kidney Stone Types

I have mentioned the problem of multiple stone crystal types in selection of trial candidates but provided little detail.

Special Crystals

Other kinds than calcium crystals – uric acid, cystine, and struvite differ in structure or cause or both.

Uric acid crystallizes in the unusually acid urine found most often in obese or diabetic people, those with gout, or kidney disease, or bowel diseases. The crystals have one cause – acidic urine – and one treatment – alkali, for the most part, and need not recur. This makes them special. Uric acid can mix with calcium crystals or form stones alone; either way, we use the one treatment for it.

Cystine stones come from a genetically disordered kidney transporter system that lets excesses of this poorly soluble amino acid into the urine. So much gets into urine the stones can grow rapidly and large.

Struvite crystals form in humans entirely because of bacteria that produce them by degrading urea to ammonia. They are infected foreign bodies. Like all such surgeons treat them. Often bacteria infect other kinds of stones so struvite mixes with them.

Drug stones – antiviral drugs are an excellent example – differ altogether from what I might call ‘natural’ stones. One must know the drug and take special steps.

Calcium Crystals

If water alone sufficed for calcium stones we would still require stone analysis to identify these three special crystals. But the trial I just reviewed showed us the limitations of water alone, so even the calcium stones need sorting out.

One cannot say calcium stone, calcium cannot make a stone. It needs a partner – oxalate or phosphate. Only analysis can tell these two apart.

Even the water trial mixed calcium oxalate and calcium phosphate stone formers together. Chemical analysis cannot quantify percentages of calcium phosphate as well as modern instruments so some patients in the water trial may have formed mainly calcium phosphate crystals. Calcium oxalate will preponderate, being most common.

You might say why care. I reply because the two types tend to cause different kidney tissue calcifications and seemingly different patterns of injury. They may resist treatment differently.

Knowledge and Pursuit of Prevention

But that is to slight the real reasons. The two types of calcium stones form under different conditions, from different supersaturations. So treatment for one need not exactly fit for the other.

Another reason to know about the stones, especially as a patient, concerns the willingness to accept treatments. Knowledge, I think, reassures people that their treatments rest on sense and aim purposefully. No one has tested this idea, that I know of. But perhaps someone should. The idea set me to describe the stone crystals in extenso, their structures, chemistry, and relationships to those water molecules that they, in forming, bid their fond adieux, and leave. I have noticed that thousands of people read the Kidney Stone Types article, evidence they seek knowledge.

Kidney Stone Matrix Proteins

Urine itself contains over 1,500 proteins. The few kidney stones we have analysed using the latest technology contained over 1,000 proteins. Many bind to calcium crystals and affect how they form and grow. I myself spent years trying to figure out which of the ones we could identify really mattered and so did many of my contemporaries.

To now, we do not have anything practical for physicians. No assays. I have to imagine this mass of molecules matters. It must. But that hypothesis is dream like because I cannot deduce a worthwhile test of it. If it mattered – I say to myself – then what?

In rodents scientists have knocked out genes for a few of the mix and challenged the animals with excess oxalate asking if loss of the protein made them more prone to crystal formation. Yes. But I cannot leap from there to humans. For example, rodents make no stones if left alone, people do.

Why, then, mention these numerous proteins?

How can I not?

Analyse Every Stone

One might think that once we know someone forms, for example, calcium oxalate stones more analyses add little or even nothing to successful treatment. But at obvious problems make that thought a poor one.

New Struvite

Every surgery poses risk of infection. As foreign bodies in the kidneys stones themselves offer lodgment to bacteria that may be passing through the urinary system. So struvite can grow over older calcium stones, or even begin on their own. The person ‘converts’ from one type of stone crystal to another. Treatment no longer stops stone growth.

Because rapidly growing, large, and laminar in appearance by x ray, struvite stones will make themselves apparent over time. But larger size means more complex surgery, and perhaps kidney injury or even sepsis from stone infection.

New Uric Acid

People age, gain weight, develop diabetes and with this urine pH falls. Treatment with alkali that might have stopped uric acid production begins late, when rapid stone growth or large stone size makes uric acid come to mind. But large means harder to dissolve, perhaps impossible. That means surgery.

Calcium Oxalate to Calcium Phosphate

This happens and probably matters. CaP stones most often arise over tubule plugs which means cell injury in tubules and the tissues around them. Growth over plaque, how CaOx stones form, appears less invasive. Tissues seem less injured.

My imagination tells me calcium phosphate stones may cause more long term kidney problems than calcium oxalate stones. If this hypothesis were true then mere observation of patients well characterized in stone composition should disclose differences in kidney function, or perhaps urine albumin loss. Perhaps blood pressure rises more. Perhaps someone might have such information.

Quite possibly potassium alkali that work well to prevent calcium oxalate stones do poorly for calcium phosphate stones. After all, they raise urine pH and a higher pH will foster the phosphate stone. No trial addresses this obvious question; one should.

Clinical Practice

If you believe my reasoning, analyse every stone. The cost for many analyses seems slight compared to, as an example, even one late neglected struvite or uric acid staghorn. But, my advice has flaws. How often do analyses surprise us? How much do many costs compared with early diagnosis of what I just mentioned? Surely people have data to answer this question. I do not. About phosphate stone formers and potassium alkali, do as you think best; we have no trial.

How Good is Kidney Stone Analysis

Less than ideal

What happens if you make a rigorous analysis of stones, divide the sample up into parcels and send them to different commercial laboratories. What will they tell you?

Ideally they will tell you what you already know. But in fact they under reported struvite and calcium phosphate – as hydroxyapatite. They also failed in to identify brushite.

Not ideal, especially since struvite means infection stones.

Not Utterly Unreliable

My own work with Joan Parks compared kidney stone content of CaP – as hydroxyapatite to urine pH and supersaturations obtained by 24 hour urine samples. Unlike work from centers that performed their own kidney stone analyses we relied on a multitude of commercial lab reports obtained over decades. Even so urine pH and CaP supersaturations tracked will with these commercial lab results.

A Reasonable Conclusion

As an inexpensive and indispensable tool, all of us need and use commercial kidney stone analysis. What we know prompts wariness about missed struvite – a most important stone diagnosis. But perhaps that argues for multiple analyses – more tries lower likelihood of missing the diagnosis.

Summary of Chapter One

The miserable fragments we call kidney stones have a complex origin in the kidneys. All but one kind contain crystals without which they could not exist. The exception, protein stones, occur rarely and I do not consider them here. Stone crystals form as all crystals from, from a solution overloaded with the crystal material – supersaturated with respect to the crystal of interest.

Kidneys can supersaturate urine by conserving water or by increasing the amounts of insoluble salt constituents such as calcium or oxalate. They can reduce the excretion of citrate, an inhibitor or change pH. The latter can be downward, fostering uric acid or upward fostering calcium phosphate crystals.

Although effective and obvious, extra fluids do not reduce new stone production completely to the baseline levels of average people. Moreover, above perhaps 2 to 2.5 liters a day of urine becomes difficult to maintain. So ideal treatments employ synergies – increase of fluids and changes in calcium, oxalate, citrate, or pH of urine as indicated in any one patient.

Since all treatments but water relate to specific crystals, prevention depends on stone analysis whenever possible. Stone crystals can change over time and I see no reason to discard stones and good reasons to analyse them. Especially, infection or uric acid stones may complicate or even replace calcium stones and be missed without analyses. Likewise for stones from drugs.

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