Chapter One: Personalized Kidney Stone Prevention

Personalized kidney stone prevention perfectly exemplifies the goals and aspirations of this modern age of precision medicine. Nowhere more than here is treatment 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 not only reduce stone formation. I have observed that patients easily distinguish this treatment from vague nostrums or imagined remedies thrown out to them by friends or busy and distracted practitioners. I believe such understanding promotes long term use, although I have no trial to prove it.

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 with idiopathic stones how to lower the relevant supersaturations and keep them low long term. For those with systemic diseases as a cause of stones, supersaturation gauges how well systemic disease treatment has lowered stone risk.

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 with greater insight once their physicians have identified those factors most relevant to their stones.

Surgical Costs Dwarf Those of Proper Testing

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. I do not need to prove this assertion by a complex cost benefit analysis. Mere order of magnitude will do.

A common 24 hour urine with fasting blood sample costs a few hundred dollars – say three hundred for an estimate. A kidney stone surgery, ureteroscopy for example, costs – about eight to ten thousand 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. Shock wave lithotripsy costs as much or more as shown in the same reference. At these rates, 30 to 40 24 hour and blood testing panels match one surgery discounting the personal losses.

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?

For the moment let’s focus on the most simple and common situation, patients who do not harbor such dangerous or complicated diseases but simply tend to form stones. Not only that, consider the least threatening possible scenario of only one single calcium stone – a kind of baseline kidney stone disease.

Being such a common and large group why not simply treat them with lots of fluids and save testing and more refined treatment for the rest?

That Has Been Tried

Before you read what follows brush up on supersaturation

Of ninety nine people who formed one calcium oxalate stone and drank so much they produced 2.6 liters a day of urine 12 formed one or more new stones in five years (Group 1). Among one hundred more just like them who produced only 1 liter of urine daily 27 formed one or more new stones during 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? Of one hundred random people 12 people will not make one or more new 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, who drank less, the numbers essentially double.

More is wrong than water could right.

Note that both curves showing the fraction of patients who formed one or more new stones flatten over time, so my extrapolation from five to ten years by doubling is perhaps overly large. If you like multiply the five year rate by 1.8 or even 1.5 to allow for a falling relapse rate and the results still predict too many stones.

The Trial Was Not Perfect

The trial enrolled patients who had formed only one calcium stone. All had formed calcium oxalate stones. But the stone analysis used chemical means not infrared spectroscopy, so to a modern eye stone ascertainment seems questionable. Some might have had calcium phosphate stones.

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.

Multiple Stone Formers Fare Even Worse

These patients had produced only one detected stone. Even so water alone in even so copious a volume as to produce 2.6 liters of urine a day left 12 people free to make one or more new stones in five years. What about treatment outcomes in people who had more than one stone, even those who received multiple treatments including medications? Might they not fare even worse despite treatment?

We have data only for those people whose calcium stones did not arise from any known systemic disease – so called idiopathic calcium stone formers. But for them we have multiple prospective randomized controlled trials whose data can tell us how well treatments can prevent more new stones.

A Review of All Kidney Stone Trials

Compared to those who have formed only a single calcium stones, treatment is a lot less effective for people who have formed multiple calcium 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 (along the horizontal axis), 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 had formed before treatment.

Results for the water trial of single stone formers and my own published observations on patients who had formed a single calcium stone are at the lower left of the graph.

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.

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. 

Why Wait?

A deeper point  – time is not on the side of a stone former. More time, more stones, a worse outcome from treatment. So evaluation and treatment should begin with the first stone.

Patients Need Personalized Treatment

Water is a partial remedy for people with no systemic disease and only one calcium oxalate stone, but 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? In some of those seemingly idiopathic calcium stone formers a full evaluation will disclose systemic causes of disease that require more complex care.

For those with more than one stone, the same. But medications often are needed because diet and high fluids cannot control new stone production.

Testing Personalizes Treatment

Gauge the Common Pathway

What supersaturations does the patient generate during the course of normal life as lived? Using CT scans and detailed medical history, how many stones have been formed? How have we excluded systemic diseases? Is kidney and urinary tract anatomy normal?

Only urine measurements can quantify supersaturation and its determinants. The only collections that actually confer stone risk on measurements used 24 hour collections so those are best. Supersaturation vary throughout the day and night so no spot collection suffices. The costs of a spot urine and a 24 hour urine are the same.

Exclude Systemic Diseases

How else but through the usual means of clinical medicine. One knows what they are, one performs the hallowed, ancient medical history and physical examination, and measures in blood and urine to make a diagnosis. One never treats any disease without diagnosis. Stone disease is a disease like all other diseases.

Know The Types of Stones

Supersaturation relate to the crystals formed. If crystals are all calcium oxalate, those for uric acid have less relevance. Likewise, if stones are hydroxyapatite, calcium oxalate supersaturation is not of prime interest.

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

Calcium oxalate and calcium phosphate stones differ in their physical character. The two types tend to cause different kidney tissue calcifications and seemingly different patterns of injury. They may resist treatment differently. So we need to tell them apart.

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 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.

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 form, 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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