I have alluded to objectives in my discussion of applied, basic, and empirical science, which was a good place for their first mention but too narrow for a proper exposition. They are in the first case an expression of need, in the second case of desire, and in the third arise from perhaps an altogether different source. Here I am concerned with objectives of applied medical science. CLASSES OF NEEDS What can be the perceived needs of medicine but treatments, prevention, tests – to aid diagnosis or prognosis, methods, techniques and devices? EXAMPLES OF EACH CLASS Consider a patient with calcium oxalate stones not due to systemic disease, ‘idiopathic’ stones. Treatments This refers to stones present; they are there and surgeons need … Continued
THE TABLE OF CONTENTS
Here is an alternative BRIEF LISTING without explanations.
A. Kidney Stones as Objects of Study
For patients and their families, a general introduction to kidney stones and the illness they produce. The purpose is to isolate stone crystals as the central object of evaluation and treatment. Because the very hardness of stones, which so buttresses their obstructing character, results from their crystals, physicians direct their treatments against those crystals in hope of preventing their growth and new formation. But to do so they must know which crystals a particular patient produces. This can best be found out by stone analysis, which is readily available and not expensive. Although simple increase of fluid intake alone can reduce the likelihood that someone who has formed only one stone will form another, it is not very effective against recurrent stones. People who have formed multiple stones benefit most from specific treatments directed against the causes of their stones.
This exhaustive and exhausting review of the crystals in common kidney stones illustrates the molecular structures of phosphate, oxalate, urate, urea, cystine, and water, and points out why urine acidity regulates formation of uric acid and calcium phosphate stone crystals. The presentation is at a high level for patients. Although it omits crystal structures and stops short of crystal interactions such as calcium oxalate or hydroxyapatite forming on brushite surfaces, physicians might find it useful as a review. This material is essential for understanding supersaturation.
With a focus on recent research publications concerning the urine proteome and the urine molecules that make up stone matrix, this scientific review links to a longer review of mine that is not otherwise available. The purpose is a convenient portal for researchers into a growing literature. Because they kinetically retard crystal formation, growth, and aggregation matrix molecules may explain why supersaturation cannot reliably predict whether stone crystals will form, and also explain why urines can remain metastably supersaturated for many days. Likewise, being so powerful, these molecules must eventually become a crucial part of clinical evaluation and stone prevention once our techniques become good enough to permit us to understand their character and relationship to stones. Aimed as scientists, physicians and scientifically trained patients may find the information interesting.
Meant mainly for physicians and their patients, this post takes on the question of what fraction of passed or removed stones should be sent for analysis. Given the primacy of stone crystals, I argue that it should be all the stones because in some people and over time one crystal type converts to another and that treatments need to change. However, no amount of forceful argument can substitute for trial data. I do not know if analyzing all stones will improve long term stone prevention. On the other hand, given the meaning of ‘long term’, I am not sure if a trial can ever be done. Perhaps some medical decisions, like this one, can best be made through deliberation, especially when risk and cost are modest.
Published work reviewed in this post suggest that commercial stone analysis laboratories vary in quality. This should interest patients, and physicians, and scientists alike. Samples of stones sent to different laboratories yield different answers concerning the percentages of the various crystals. Some crystal forms, such as struvite, can be missed on occasion. This is important because struvite implies urinary infection. On the other hand evidence is put forward that commercial analyses cannot be altogether without rigor as they correspond with tissue changes in kidneys determined by intra-operative biopsies. Likewise stone phosphate percentages obtained from routine commercial laboratories correlate very well with calcium phosphate supersaturations measured in the urine of the patients who produced the stones.
This article could have been listed under Pathophysiology of stones, because it does indeed detail what happens to acutely obstructed kidneys, but I put it here as it is a cardinal manifestation of the stone itself and perhaps its most noticeable, famous, and frightening consequence. This is a foundational article, necessary reading.
B. How Stones Form in Kidneys
In a form intended for scientists, but accessible for physicians and some patients, movies and still images illustrate the manner in which calcium oxalate stones form as overgrowths on renal papillary interstitial hydroxyapatite deposits – so called plaque. Dr. Andrew Evan pioneered in the delineation of this process and brought here a fine summary of more than a decade’s effort. Growth on plaque is the only proven process for formation of clinically relevant human kidney stones. Other processes have proponents and enthusiasts, which include the present writer, but lack complete proof that they produce stones large enough to obstruct the urinary tract. The remarkable role of calcium phosphate crystals in forming the calcium oxalate stone can be overlooked: Plaque is hydroxyapatite, the initial attachment of stone over plaque is hydroxyapatite. Calcium oxalate only appears as an overgrowth by about 70 microns out from the attachment site. So formation of calcium phosphate crystals, meaning levels of calcium phosphate supersaturation, are of great potential significance in routine calcium oxalate stone formers.
Ciudin et al (JOURNAL OF ENDOUROLOGY, Volume 28, Number 8, August 2014, Mary Ann Liebert, Inc. Pp. 1016–1021) followed for 7 years a cohort of people without stones who had routine CT scans. A particular level of papillary density as estimated by simple HU assessment in a 0.1 cm2 region of papilla devoid of obvious crystals predicted the few who went on to make stones as opposed to the majority who did not. The comments refer to a 2008 paper by Professor Brian Eisner which showed more or less the same thing. This post is aimed squarely at clinicians, although scientific scholars might want to consider what kinds of research might be done using the method.
Kristin Bergsland has posted her novel hypothesis that activation of TLR-4 receptors in thin limbs of the loops of Henle might promote plaque. This will interest scientists. The difference between mere conjecture and hypothesis lies in their predictive power. Kristin proposes a sequence from which one can deduce predictions which are necessary if the hypothesis is true. These are useful predictions because they can be tested experimentally with techniques that exist at the present time. Failure of key predictions will falsify her idea. The importance of doing some of these is obvious, and I hope her post stimulates new experiments. I believe this will become an important area of kidney stone research.
Like its companion piece, this article by Professor Andrew Evan details the crystallizations found in the kidneys of stone formers. Although aimed most at scientists, physicians and patients will have reasons to want to read this work. Unlike plaque, which does not seem to damage kidney tissue, tubule plugs destroy the lining cells of the terminal ducts of Bellini and the inner medullary collecting ducts – the final portions of the nephrons. Surprisingly, kidney function as we measure it clinically appears well preserved, although one does find scarring and loss of nephrons in the cortex of the kidney as well as the papillum. Perhaps kidneys are resilient enough that damage to the terminal portions of the nephron is tolerable. Perhaps the lesions are small and patchy enough that the total sum of injury is too small to cause loss of kidney function. But even so, there is damage, and patients with plugging warrant treatment to prevent more crystals even if stones have been few.
C. Supersaturation and Inhibition
1. A Primer
This is an important essay, perhaps the most central of the present collection, and written especially so patients can fully understand it. It tells about what supersaturation is in general, why kidneys might have evolved to create supersaturated urine, and how measurements of supersaturation can be used in stone prevention. Water conservation permits terrestrial life, and an internal calcium phosphate skeleton demands some traffic of calcium and phosphate through the body to accommodate to bone turnover. That traffic is from food, through the intestines and blood, the kidneys, and into the urine. There exists no effective offset to high urine calcium concentrations. The proposal that kidneys protect themselves by reducing water conservation when urine calcium concentrations rise failed when tested in our own experiments.
Drinking extra water – more than is needed to replace losses from sweating and respiration – signals the kidneys via a fall in vasopressin to reduce water conservation, and this reduces supersaturation. Likewise for medications or diet changes that reduce urine calcium or oxalate. Since stones are what they are because of their crystals, and supersaturation is the force that drives crystal formation and growth, supersaturation and its management are the central issues in stone disease.
This essay was written for physicians. I detail the principles that link supersaturation with classical thermodynamics wherein supersaturation takes the form of energy and forces that produce it take the form of work, but stop short at the mathematical formulations. The unique stability of highly supersaturated urine samples is ascribed – I believe correctly – to the abundant and powerful kinetic inhibitors of the urine proteome. In men and women, urine supersaturation with respect to the pH dependent crystals – calcium phosphate and uric acid – are higher in stone formers than in normal people. Likewise for the pH independent calcium oxalate crystal in women. But in men there is an anomaly in that calcium oxalate supersaturation of patients who form calcium oxalate stones is no higher than in normal men. This is ascribed to inhibitors but without evidence. The steps in using supersaturation clinically are detailed here as nowhere else: Is the patient an active stone former? Do we know the crystals in stones? Was the urine collected so as to represent the true supersaturation during the majority of life as lived?
A recent, exact, and uncompromising review of saturation is at the center of this technical presentation aimed at scientists and interested physicians. As well, a few recent research papers seemed relevant and I reviewed them. As though like fate, supersaturation determines the ultimate outcome of a solution: It will collapse, some day or other, into two phases – it will make crystals. ‘Some day’ is the secret. If you try to produce simple solutions saturated like urine, they will crystallize as you add in the ligands. Once again, it is the urine proteome that permits urine to maintain stable supersaturations. It is a fate delayed, as Odysseus was from reaching Ithaca, but one no amount of intervention, even by so principal a god as Poseidon, could delay forever. Every physician who uses supersaturation might enjoy the review this post embodies.
Cumbersome perhaps, unreliable against the complexity and sheer chaos of life as lived, unlikable even, extra fluid throughout the day and even at night is the most elegant of therapies. This essay is specially written for physicians but patients may enjoy it as well. Since urine dilution specifically undoes what the kidneys do by extracting water to concentrate urine, no other single treatment can effect so exacting a reversal of the central step in pathogenesis of supersaturated urine. Because of chaos, forgetfulness, and almost universal dislike high fluid intake can fail despite its outstanding mechanistic virtues. In fact, no long term trials have ever proven its worth except in delay of second stones in patients who have formed only one stone.
This entry uses research data to demonstrate how supersaturation varies throughout the day and night, and how it varies with urine volume in normal people and stone formers. From the data, I have extracted some estimates that permit calculation of a reasonable fluid prescription.
Being one of the three drugs used to prevent stones, potassium citrate deserves an extended presentation, and this is the first installment. I think this article will interest everyone concerned with stone disease. The trials show efficacy and are convincing, at least to me. The main points are numbers of cases who did and did not get stones with and without treatment. Anyone who uses numbers for work or play can understood these results perfectly. Although I favor fluids as a base for treatment, one cannot be always vigilant. Potassium citrate is one of three medications which can take up some of the burdens of stone protection not everything needs to depend on consistent high fluids alone.
Citrate can reduce stone formation by binding urine calcium in a soluble complex leaving less free for formation of calcium oxalate and calcium phosphate stones. It can also inhibit the process of calcium oxalate and calcium phosphate crystal formation. This article tackles the first issue, of binding, and shows how binding works. I think everyone will be interested since citrate is a widely used medication for stone prevention. Most scientists in our community will find this a nice review of what they already know. Physicians with an interest in how things work – most physicians, I think – will enjoy the review for that reason. Patients are the ones who take this medication. So I really wrote it for them. They have every reason to want to know how the stuff works, or seems to work, in stone prevention. Alas, one cannot tell this story without some chemistry. But patients are smart and can figure most things out very well indeed.
This article tackles the second issue, crystal inhibition. The process is much the same as how citrate binds calcium, except here citrate is binding calcium atoms that are already part of a calcium kidney stone crystal like calcium oxalate or a calcium phosphate like brushite or apatite. These crystals like to grow in a certain way which I outline here for you. Citrate binds to calcium atoms the way oxalate or phosphate does but is the wrong size to fit into the highly organized crystal structure. It disrupts the orderly creation of an aligned series of repeated calcium – oxalate or calcium – phosphate motifs, with the result that growth of crystals in their prefered direction is slowed or even stopped. The power of inhibition makes citrate a grand treatment, if cumbersome, expensive, and prone to side effects. Being a treatment, everyone will have some interest in how citrate works. The article is a bit heavy, however, because I could not find ways to simplify it.
Charles did much of the best work on this treatment. His papers need to be remembered and read. Likewise, his work to bring a pill form of the drug to the public made this treatment practical. He built a remarkable program in kidney stone research at UT Dallas, and has trained a number of outstanding academic physicians. Charles is a wonderful scholar and a good friend of mine, too.
The upper limit of metastability or Ostwald Limit is determined experimentally using methods that cannot as yet be applied to clinical practice. I and perhaps everyone I know have ascribed the position of the limit – generally far above the prevailing supersaturation of the urine – to the mass of large molecules in urine, the so called macromolecular inhibitors. A new analysis of data John Asplin and I published decades ago suggests we may be wrong, and that citrate and perhaps inorganic pyrophosphate may account for much of it.
D. Clinical Practice and Patient Management
In an uncharacteristic moment of person disclosure I wrote this post about the manner of my own stone prevention practices. It is perhaps mostly for physicians. Perhaps the most interesting aspect of these practices is how dependent they are on the subsidy of a professor by society, a subsidy that permits me to give my patients far more time than would be usual these days. At least in my experience, which is at best an unreliable guide to the truth, stone disease is so often a result of heredity crossed with habit and chance that for its treatment I feel compelled to learn about the details of life lived – a slow process of learning! I show a case in point but almost any would be the same. I called the post ‘Art of Stone Prevention’ meaning it is a made thing, which I do believe pertains to what physicians do.
If high fluid intake has an elegance, being an exacting reversal of the process of renal water extraction that produces supersaturation, it has a burdensome and tedious nature. This lighthearted and skillful post for patients, by Jill Harris, offers alternatives that make water drinking, if hardly in a class with Summer blueberries or chocolate peanut butter ice cream, at least not intolerable and maybe fun, for some people at least.
Here is a complex area littered with poor information. This article, for patients and physicians seeks to tease out facts from fiction. Coffee and tea, for example are shunned by doctors and patients as stone provoking even though excellent epidemiological research in men and women make the exact opposite point. It is true that epidemiology cannot prove causality, but lack of association is a point against cause, so this kind of research is forceful when negative. Jill Harris makes her way through all of the usual items, grades them from what data we have into neutral, bad, or perhaps beneficial, and makes up an pair of menus, each one for a full day with considerable variety.
For everyone. If the deep roots of supersaturation in classical thermodynamics is one pole, surely this must be the other – an ultimate pragmatism. Somehow an inexpensive and ancient stone remedy has become too expensive for at least some people to afford. The cause: Some combination of price increases and change in insurance coverage. Fortunately there are a lot of workarounds, which I put into this post. The comments are at least as useful as the post itself.
We have devoted a page to this and invite patients, their family members, anyone interested to submit questions. What to do for stone prevention is a medical issue. How to implement what has been recommended is not so much medical as simply practical. Jill Harris, a nurse who has had a large experience in counseling patients for Litholink, volunteers to run this page. Questions are in three areas: Lifestyle; Fluids; Foods.
Written for patients, but perhaps interesting to their physicians this article presents my own ideas distilled from nearly 50 years of clinical experience with kidney stone prevention. Patients can do a lot before their medical visits so that the visit time is used for counseling and planning treatment, not wasted in a futile and frustrating search for crucial information. Afterwards, during the long years of treatment aimed at prevention, I believe a cycle of treatment with interim testing is ideal, and my own published observations suggest that the approach will yeild excellent outcomes.
E. Unproven Tests and Remedies
The web is all at once a miracle and a mess. When I read through the very many kidney stone sites, I am delighted by the best of them and appalled by the worst. This little treasure is rather old, and as silly as possible. So much so that Dr. Anna Zisman took on the evidence and makes clear that it is at best a benign waste and at worst an evil habit to treat stones with volumes of COKE and – how strange can one get? – canned asparagus! For everyone with a sense of humor.
F. Science and Medicine
This entire section reviews established but not well known principles of modern science as they would apply to and be used for advancement of knowledge concerning kidney stone disease. It is potentially interesting to all people interested in the intersection of scientific research and medicine.
Theory is the word for the entire collection of what is taken as true for a given area of human knowledge, especially in science. I have created this site as an eventual repository for much of what is taken as true for kidney stones, but here offer only the general outlines as a kind of schematic map. But like a map, it is complete in itself and contains at least the places in which what is taken as true can be fitted in.
Natural athletes, I have been told, give little thought to how. When the ball come, or they hit the water, they just do it. Unnatural athletes need to learn how. From this silly metaphor, guess who I am. No end of study about how science works has made a difference for me. Once I got used to the odd ways of thinking needed, I began to think better. The great naturals do not need such getting used to things.
Medicine is all about applying what is already known to individual patients about whom much is to be found out. This makes it a topsy turvy place. Scientific techniques like hypothesis testing is used, sometimes, as is empirical science, but all that is preliminary to simply figuring out what of the available treatments is right for that patient. So, for what reason would a sane physician want to know basic science findings as an enhancement of clinical practice. I am not speaking about being knowledgeable, or enjoying science, I mean from a practical point of view what would be the value.
If you have not been there, not done it, the objectives of a scientific excursion – inquiry in fancy terms – seem as obvious as a shopping list: We need to know this or that, and that is what we will find out about. The reality is like a shopping list. You cannot set out to buy what cannot be bought or what you cannot afford; you should not set out to buy what you cannot use, what no one wants, or what no one could learn how to use. You should not set out to buy what can only be bought where you cannot go right now – Norway, for example. It is even trickier: researchers are paid by the public to bring back presents – new knowledge. Picking the right present is hard! It takes taste and a fine sense for others.
Part of the way science enters medicine is this way – committees of mostly statisticians are empaneled by agencies of the government, or perhaps as in this case one of the colleges of medicine to determine the fitness of evidence concerning treatments and tests. This committee was no worse than most, but more naive. Not so much concerning the idea that fluids are a good thing, but in offering a kind of side opinion that one need not measure urine volume before or during treatment. That is silly. But underlying the silliness is a hidden assumption I quarrel with: What has not been tested is not true. We cannot and will not test everything. For example, we will not test whether when giving fluids for stones prevention is better or not if one measures volume. No trial has done this, and who would do it?
As everyone in the field knows, thiazide, potassium citrate, allopurinol and reduced sodium high calcium diets all have beneficial effects in trials. This parsing of the trials came to the same conclusion but offered the same slightly off kilter thought that no trial has proven that measurement of urine or blood chemistries affects the outcome – numbers of new stones. It cannot in these trials as all of them employed measurements. One is not likely to undertake a trial without them. This guideline statement has two hidden assumptions: What has not been tested is not true; one can ignore well established science if its practical application has not been tested. There are not identical. For example, one uses thiazide to lower urine calcium excretion and the drug is therefore not likely to work if urine calcium excretion is, for example, low.
This article explored the details of how medicine and science actually interact so as to bring about new knowledge and use that knowledge for patients. The most simple example from stone disease is used as a framework for the analysis. Marriage is the metaphor I came up with, being a condition of partnership and intimacy between dissimilar people which has a potential for creation of something new.
Two other criticisms of these flawed guidelines are listed just above in the table of contents. This one is special because Dr. Goldfarb was a peer reviewer of the manuscripts of these guidelines, rejected them for lack of merit, and found them published anyway. Here, in his letter to the Governors of the ACP he tells the backstory of this poorly executed guideline process, and warns the ACP and all of us that the outcomes for patients may be unsatisfactory.
G. Pathophysiology of Stone Disease
The mechanisms by which kidneys remove acid loads are fully activated in almost all people who live the ‘First World’ because their diets are high in proteins which impose an acid load. The effects of this activation include conservation of citrate which is a potential alkali. Dosing with citrate or any other alkali neutralizes all or part of diet acid loads, and releases the kidney from its perpetual demands. One result is a higher urine citrate. The pathways are very elaborate, and that elaboration may account for the variable effects of oral alkali. In some people urine citrate rises and urine pH does not rise appreciably. In others, urine pH rises and citrate hardly does. Most people are in between. A lot more research would be valuable here.
The physiology that controls urine calcium rests upon that which regulates urine sodium. The two are that closely tied to one another. One consequence of this linkage is that control of urine calcium and therefore of supersaturation and stone risk begins with reduction of sodium intake, if necessary, to the levels presently considered desirable in the US – 1500 to 2000 mg. How the linkage works requires we understand how sodium physiology itself, and this article was written for that purpose.
If your urine calcium excretion resides in the upper end of the continuous distribution of excretions among men and women, not the extreme of the upper end but just somewhat above the median, your risk of stones and of bone disease is higher than the average. It is like blood pressure, and the level of detectable stone risk is not very high – above 200 mg/day, men and women. Many systemic diseases cause hypercalciuria and stones, and this article reviews the more common ones. Primary hyperparathyroidism is featured, some rare single mutations are mentioned, and the very common idiopathic hypercalciuria is introduced for the first time on this site.
Common, familial, surely genetic this is essentially a high urine calcium excretion unexplained by any recognized systemic disease. It is like high blood pressure or tallness, being just the upper end of a continuous distribution, but like high blood pressure and unlike tallness high urine calcium causes diseases – stones and bone disease. This long and complex article presents the links to stones and bone disease, evidence for a genetic basis, calcium absorption and bone balances, and renal pathophysiology. What emerges is an exaggeration of normal physiology in which bone, GI tract, and renal tubules all participate. The distinction between absorptive and renal hypercalciuria disappears for the most part in that both organs participate together most of the time. Perhaps the strongest implication of what is known is that low calcium diets are inadvisable except under special circumstances, whereas lower intakes of sodium, sugars, and protein appear safe and effective.
WHAT IS THE QUESTION? I understand that some physicians are skilled basic scientists, and that many physicians enjoy reading about basic science. But how does a knowledge of basic science benefit the patients of physicians who have such knowledge? There are two parts to this question. How can being a basic scientist benefit a physician in the practice of medicine, and how can a knowledge of the results of basic science benefit a physician in the practice of medicine. Of these two, I mean to consider only the second: How does a knowledge of basic science results benefit the practice of medicine. Of course, here, I mean practice of medicine concerned with kidney stones – the disease within the province of this site … Continued