Chapter One: Personalized Kidney Stone Prevention

Personalized kidney stone prevention perfectly exemplifies the goals and aspirations of this modern age of precision medicine. Nowhere than here is treatment more specific to a given patient. Computer – like and driven by exacting physical laws, stone crystals respond to forces we can quantify in homely but surprisingly informative 24 hour urine collections.

Crystal specific, patient specific treatments work. They reduce stone formation. And, they foster long term adoption by patients who can understand their basis and therefore believe in the treatment as more than some vague nostrum or imagined remedy thrown out to them by a busy and distracted practitioner.

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

Personalized Kidney Stone Prevention

Physical Chemistry Guides Proper Kidney Stone Prevention

Crystals produce kidney stones, and kidney stone crystals form because of supersaturations specific to those crystals. Modern laboratories can measure these supersaturations in 24 hour urine collections along with the key components in the urine that control the supersaturations. By diet and a few medications wisely combined physicians can show patients how to lower the relevant supersaturations and keep them low long term.

Patients and Physicians Play Coordinate Roles

Patients determine the success of personalized kidney stone prevention. Only they can maintain needed hydration and diet changes, take medications regularly, and collect the all important 24 hour urine collections under conditions that approximate conditions of life as lived. Although only physicians can judge if new stones form, they depend for that judgment upon patients to report when stones have passed. Likewise, patients can easily read their own 24 hour urine results but only after their physicians have identified those factors most relevant to their stones.

Surgical Costs Dwarf Those of Proper Testing

Although rarely fatal, or even highly dangerous, stones cause recurrent painful attacks that lead, in turn, to ER visits and costly, dreaded surgeries. No amount of 24 hour urine or blood testing can matter either financially or in time spent when put up against the enormous cost of even a single surgical procedure. A common 24 hour urine costs a few hundred dollars. Kidney stone surgeries invariably cost many thousands of dollars, even tens of thousands of dollars each, to which one must add lost work and the debilitating effects of general anaesthesia, postoperative pain, stents, infections, and postsurgical visits to physicians.

Inadequate Testing Can be Dangerous

Perhaps the most serious mistakes occur when stones, because not fatal, are neglected through inadequate testing. A few causes of stone disease, such as severe hyperoxaluria can destroy kidneys. Others like primary hyperparathyroidism or renal tubular acidosis can do the same. Rare but dangerous inherited diseases lurk in any kidney stone population. This makes empirical and unguided kidney stone prevention as hazardous as it is misguided and to failure doomed.

Why Not Just Lots of Water?

That Has Been Tried

Before you read what follows brush up on supersaturation

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 (Group 1). 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. SS CaOx was 9.9 in the low flow and 2.6 in the high flow group. SS CaP was 1.58 in the low and 0.48 in the high flow group. Excellent and predictable results.

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 Is Not Enough

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.

The Trial Was Not Perfect

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 seems questionable. Because stones in kidneys would mean more than one, they excluded all who had them. But their means of exclusion was simple x rays not CT scans. So small stones could have hidden in kidneys undetected. High blood pressure employs low sodium diet and thiazide drugs that also reduce stones, so blood pressures needs be normal.

Even though a few stones might have hidden, there were way too many in the people with 5 years of a 2.6 liter daily urine volume.

Multiple Stone Formers Are Even Worse

These patients had produced only one stone. Even so water alone did not fully prevent new ones.

A Review of All Kidney Stone Trials

Treatment is a lot worse for people who have formed multiple stones. When treated, far more than 12 percent relapse – form a new stones – in five years. This despite hydration and medications.

This figure shows the treated patients in a number of published trials. The details can be found in the parent article. 

The main message: As the number of stones produced goes up from one to 10 or more, the percent of patients who relapse rises from 10 – 12 percent to 20 to 30 percent. More or less, the percent who relapse increases proportionally to how many stones were formed before treatment.

Why Does this Happen?

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

The Main Point

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 water treatment article in the link above. 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. So those destined for a bad outcome had idiopathic hypercalciuria, a well known personal risk factor. 

Patients Need Personalized Test Guided Treatment

Water is a partial remedy for people with only one calcium oxalate stone, not sufficient for the long term. Even if they maintain a very high urine volume of above 2.6 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 more than one stone, the same. But medications often are needed because diet and high fluids cannot control new stone production.

You Must Know The Type of Stone

Special Crystals

Other kinds than calcium crystals – uric acid, cystine, and struvite differ in structure or cause or both and we treat them differently from calcium oxalate stones.

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.

Different Calcium Crystals

If water alone sufficed for calcium stones we would still require stone analysis to identify three special crystals.

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.

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.

Many Paths to Stones

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.

Treatment Synergy Requires Proper Testing

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. Only blood and 24 hour urine testing can tell what is indicated in any one patient, and also what treatment has accomplished.

Stone Analysis is Crucial

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.

Stone Prevention is Precision Personalized Medicine

Stone prevention exemplifies the best features of precision medicine. The crystals arise from specific supersaturations we measure in simple 24 hour urine samples and can reduce with healthy diet changes and a few medications that have proven their worth in trials. No two patients are quite the same, so each needs personalized care – stone analysis and 24 urine testing along with blood tests and clinical assessment to exclude systemic diseases.

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