Unlike Zeus, or Athene, Janus did not come down to the Romans from the Greeks. Instead Janus appears to have originated in myths concerning what may have been an actual person present very early in Roman history and later deified. Janus presided over beginnings and endings, over gateways and doors, and was invariably dual in nature.

Like the idiopathic calcium oxalate stone formers, these are people whose stones are composed of calcium crystals and who have no systemic disease as a cause of their stones – therefore ‘idiopathic’ stone formers.

But unlike the calcium oxalate stone formers, their stones contain predominantly calcium phosphate crystals. And unlike their more unitary counterpart, calcium phosphate stones can be one of two different kinds – brushhite or hydroxyapatite, and to this time no one knows why. Note that ‘carbonate apatite is often used interchangeably with hydroxyapatite.

You might think this kind of technical detail too precious for serious attention, but it is not. Calcium phosphate stones are a different kind of disease from calcium oxalate stones, brushite and HA stone formers different from one another, and that is why I am writing this article.

The Problem of Naming

Of course, the distinction between the idiopathic calcium phosphate and calcium oxalate stone formers is identical whichever direction you approach it, and in the past the dividing line was always at 50%. If the average calcium phosphate content in all stones analysed was 50% or more, we have classified patients as having calcium phosphate stones.

In my article on idiopathic calcium oxalate stone formers, I used this distinction but pointed out that the distribution of calcium phosphate in calcium stones supports a lower calcium phosphate percent as a dividing line. For this article I shall continue to use the current 50% cut point, but mention here, and perhaps elsewhere, that in the long run it is a very arbitrary demarcator and a lower one would probably be more stable.

Unlike idiopathic calcium oxalate stone formers (ICSF) idiopathic calcium stone formers (IPSF) are not a single coherent group. A majority have hydroxyapatite as their stone CaP mineral admixed with variable amounts of calcium oxalate (CaOx), and these 2 crystal types make up their stones. We call these hydroxyapatite calcium phosphate stone formers (HASF).

The other IPSF have brushite their stones and we call them BRSF.

We and others have separated BRSF from HASF because of the oddness of their stones, and that was a good idea because, as I shall show you, BRSF differ from HASF in ways beside these distinctions about crystal type.

Brushite abundance is not distributed like HA abundance. Although most stones have no brushite, patients who have brushite in any stone usually have a majority of brushite as a stone crystal. So whereas we differentiate ICSF from HASF using the 50% criterion, we separate BRSF from others by having any brushite in a stone.

CaptureSo, after all these words, we set in one place ICSF, who have over 50% of stone mineral as CaOx and no organic stone crystals like cystine or uric acid, or any struvite from infection.

In another place we set HASF who have over 50% of stone mineral as HA along with absence of the same organic and infection crystals. In the third category are those with any brushite, who we set apart as BRSF.

We therefore have four labels to keep track of: ICSF, BRSF, HASF, and IPSF which includes BRSF and HASF lumped together. This latter occurs in series where the BRSF distinction has not been and cannot be made for want of information.

The table above shows our experience. ‘CaP’ are IPSF. BRSF and HASF (labeled CaP(b) here) are about equally abundant. But ours is a referral center that tends to attract the more complex patients, and BRSF pose complex problems of management. In a more general setting BRSF would be much less common than HASF.


The relative frequencies of the three idiopathic calcium stone formers in our series of well studied patients (Table above) show a marked preponderance of calcium oxalate stone formers, more male than female. Notice that female abundance is higher in the CaP(b) (HASF) group than the CaOx group (*) but the BRSF not different from ICSF, having a surplus of males vs. females.

A more dramatic way to visualize this marked relationship between sex and stone CaP percent is to graph it.

Capture 2As the percent of stone CaP is increased as a cutpoint, the numbers of patients (heights of the bars) falls, showing the generally higher frequency of CaOx stones, and the relative fraction female (black bars) as compared to the males (gray bars) rises. The black dots connected by lines are the percent females in each of the 8 stone CaP% categories.

Even so, it is only at the highest CaP% that females predominated over males in frequency; at the next lower octile (90-99% CaP) females were 50% of the total.

So, at least in our decades of work, calcium stones are more a disease of men than women, and women come to predominate over men in frequency only among the purest CaP stone formers.

This graph makes a subtle point. Note that at CaP% values of 20% or less the fraction female is very low, but rises steeply in the third octile of 20-50%. This accords with the distribution of stone CaP% reviewed in the calcium oxalate stone former article. At about 20% or more phosphate, one encounters a break in the distribution of phosphate contents in stones (seen in the CaOx article) and in the percent females.

This graph blurs the sex distinction because we used stone CaP% from both HASF and BRSF cases. Looking back, today, I would have left the BRSF to one side, which would have made the female preponderance among those with high stone CaP % more marked.

Sex and Age

The Mayo Clinic runs a kidney stone analysis laboratory to which are sent about 50,000 stones yearly from stone rates and male to female stone and population ratios from Lieske
around the US. In 2010 it received 48,446 stones and of these 43,545 were the first submitted to the lab for that person. From these stones, the group reports the distribution of stone type by sex and age, a very valuable contribution.

Numbers of Stones

I have made a graph from Table 2 of their publication, and show it at the right.

In the US, males slightly surpass females in frequency at younger ages (blue dots) but by about age 30-39 the two sexes are present in equal numbers. Thereafter, the proportion of males slumps progressively as men predecease women, something most men understand all too well, and women, too. For all ages, the ratio is just under 1. I put the blue dots here as a reference point for the blue bars; both show male to female ratios, one of the sex ratio of the whole population the other of the ratio of male to female stone formers.

Stones vary widely about these ratios.

The fraction of all stones (red dots; scale along the right axis) for both sexes combined is highest from age 20-69, with only a small fraction in childhood or old age.

In childhood men have slightly more stones than women (blue bar is above 1.0). Thereafter, in the teen years and up to age 39, women predominate over men (blue bars are below 1.0, at the dashed line). After 40 men predominate, increasingly, until at age 90 and more the two sexes, in this and perhaps most things, come into a near perfect alignment. As an average over all of life, men have more stones, which appears to be because of their midlife excesses (Height of the ‘ALL AGES’ bar above 1.0).

Types of Stones

sex and age vs stone type from lieske

The men are on top, women on the bottom of this picture to the left.

Stones were classified as CaOx if more than 50% so composed, hydroxyapatite (HA) if more than 50% so composed: The same criteria I have both criticized and employed. Any brushite and it was classified as a brushite stone. Uric acid in any amount meant the stones were classified as uric acid stones, and likewise for any struvite or cystine, This is the system I have used on this site.

CaOx stones obviously preponderate for both sexes over the entire range of ages, but less so in women who have far more HA stones than men just as we found and I showed in the preceding table from our study group.

The HA predominance of stones in women occurred mainly between ages 20 – 39. At ages 20-29 stones were about evenly split between CaOx and HA whereas among men HA was never more than 20% of stones. With age, HA stone frequency falls in both sexes, so that most men, and most older women (over 50) have CaOx stones.

One might think there is some biology at work here, but like all features made out in stone that biology or cause if you like can only be inferred. I think it is urine pH that is higher in youth than age for reasons I will try to sort out in another and as yet unwritten article.

Brushite stones, in both sexes, are very uncommon. You can see them as triangles along the bottom of both graphs.

Struvite stones, which always arise from infection with bacteria that possess urease, are a bit more common in women than men, a fact known for ages. The enzyme urease hydrolyses urea to ammonia and carbon dioxide, which leads to a witch’s brew of high pH, and high ammonium ion, carbonate ion, and phosphate ions which together spontaneously produce struvite (magnesium ammonium phosphate) and carbonate apatite.

This latter sometimes leads people to think that subtle infection might raise urine pH in women, who are more prone to infection and struvite stones, and by raising pH promote HA stones. This seems contradictory to the graph just above, because struvite stones increase with age in women just as HA stones have fallen from their peak, and struvite stones show no peak to correlate with the peak in HA stones in women age 20-40.

cappercent vs decades from parks phosphate paperTime and Shock Wave Lithotripsy

We (left hand figure) and others have noted an increasing percent of CaP in stones over the past 30 years. In women (black dots) CaP percent is always higher than in men, but in both it has risen. For those of a quantitative bent, the time trend of stone CaP tested by ANOVA with post hoc contrasts was significant for both sexes, and women were higher than men throughout.

In the publication, we tried to link phosphate stones to use of alkalizing agents like potassium citrate but swl and stone capcould not. However, we found a distinct relationship between CaP percentage and numbers of shock wave lithotripsy procedures.

The number of shock wave procedures per patient adjusted for the number of stones and the years of stone disease rose with the percent of CaP in stones (Panel A of the figure to the right) and the percent of CaP likewise adjusted for number of stones and duration of stones and sex rose progressively with the number of shock wave procedures (Panel B of figure to the right).

Not shown here, but of interest, the number of shock wave treatments was higher among BRSF than HASF suggesting a link between shock wave treatment and brushite stones.

One might infer from this set of graphs that the advent of shock wave lithotripsy caused the increase in phosphate stones, and there is nothing to contradict the idea. In fact, the very physiology of phosphate stone formation and the effects of shock waves on kidney function strongly support that idea as I shall show you.

Mechanisms of Phosphate Stone Formation

Correlates of Stone Phosphate Content

I have already shown that stone crystals parallel urine supersaturations. Essentially, IPSF of both sexes cluster in regions of high CaP supersaturation whereas calcium oxalate stone formers cluster in regions of high CaOx supersaturation and lower CaP supersaturation. We did not separate BRSF from HASF in this paper, as higher pH promotes both kinds of crystal.

determinants of phosphate stones sixplotCaP supersaturation will depend upon urine volume, urine calcium excretion, urine phosphate excretion, urine citrate excretion (calcium binding by citrate lowers supersaturations) and above all urine pH. 

Here, from the same paper as the time plots, is the relevant urine chemistry.

The all important CaP supersaturation is near 1 among patients with 1% or less CaP (Upper left panel) and rises substantially in the 1 – 15% CaP group and thereafter progressively but at a slowing rate with higher CaP percent. Women (black points) are lower than men.

Urine pH is remarkably low in the 1% or less groups, and rises progressively with CaP percent up to a plateau of about 6.3 for the highest CaP groups. The sexes overlap in their urine pH values.

Urine calcium, driven by idiopathic hypercalciuria exclusively in these patient, because they are all idiopathic calcium stone formers, is lower in women than in men and peaks at about 50% CaP in both sexes. In fact, among women (black points) with 1% or less CaP urine calcium is remarkably close to 200 mg, which is the threshold for increased stone risk. 

Urine volume is perhaps a bit higher in the high CaP percent patients (left lower panel). Volume is low enough in females with 1% or less CaP in stones to confer stone risk. Urine phosphate excretion and citrate excretions (right lower panel) show a very weak and variable relationship with stone CaP in men but a more noticeable one in women.

In a general linear model, the main correlates of CaP percent were urine calcium, volume, and pH in men, and urine phosphorus excretion, citrate excretion and pH in women; urine pH is the common element between them.

These correlations are not just associations because the physical chemistry of calcium phosphate crystallization is well known. Calcium can combine efficiently only with phosphate that has two free oxygen atoms – atoms not occupied by protons – and at pH 6.8 about half of the total phosphate is in fact divalent negative – has the two open negatively charged oxygen atoms. So that pH is so powerful a force, and interaction with urine calcium, volume, and phosphate is not mere statistics. Rather the statistics confirm what physical chemistry predicts and give us confidence that there are few if any oddnesses in human urine that somehow make standard chemistry inapplicable.

Conversion From CaOx to CaP Stones

We have known for a long time that some patients convert from ICSF to stones of higher CaP percent, the latter often enough to alter their classification to HASF. The opposite, conversion from HASF to ICSF must not be very common at all, as we have not observed any cases to report.

If high urine pH is a cause of CaP stones by raising urine SS for CaP, then urine pH and SS CaP should be higher in patients who increase stone CaP percent at a time before their stone CaP percent increases, in other words the ’cause’ must precede the ‘effect’.

In order to test this prediction, we collected all usable cases, which had to be ICSF who had two or more stone analyses, and had initial laboratory evaluation as well as clinical follow up data.

From 4767 patients in our program we found 445 candidates. From these we selected all who had an initial stone CaOx percent >50% and a last stone CaP% at least 20% higher than that of the first stone (62 patients, labeled T, for transformers). Men and women were combined because we had so few cases.

Of these, 26 had had their initial three 24 hour urine studies before they passed the stone whose CaP percent was at least 20% higher than their first stone – in other words up to the date of that stone which had a 20% CaP increase all stones were >50% CaOx.

the 26 converting patients with pre conversion labs TC groupThese rare but instructive patients were labeled TP for transformers with prior laboratory work – before they transformed. Finally we chose as controls from the original 445 cases the 181 patients whose first stones were >90% CaOx and who increased their stone CaP percent <20% between the first and last stone.

This figure shows only the most definitive 26 TP cases and the 181 controls.

Stone CaP percent was higher at baseline in TP (gray circles, upper left panel) but still less than 50%. As shown in the upper left and middle panels, the 26 TP patients during followup (black circles) increased their stone CaP markedly whereas the controls (gray triangles) hardly changed; this is simply because of how we selected.

Urine pH before treatment and before conversion (upper right panel) and during treatment (lower middle panel) was higher in TP (black circles) than controls, even though both groups would have been classified as CaOx stone formers. During treatment, likewise, urine pH and CaP SS were higher in TP than controls.

So high pH and higher urine CaP SS precede conversion to increased stone CaP percent, meaning these could be the cause of higher stone CaP not simply an associated trait. Add to this that supersaturation is the definitive driving force for crystallization, and the case for causality is enhanced.

ESWL was once again detected as an associate of conversion. 112 of the 136 total cases with no ESWL procedures were controls, whereas only 21/41 cases with >2 ESWL were controls (X2=17, p<0.001. Furthermore, a predominance of ESWL procedures preceded the final stone (not shown here but shown in the paper), meaning ESWL could have been a causal factor.

The Physiology of Post Shock Wave Kidneys

The haunting excess of shock wave procedures among CaP stone formers and those who increased their stone CaP percent led us to the idea that perhaps the ESWL procedure itself alters renal physiology in a way that might increase urine CaP SS: increased pH, calcium, or perhaps both.

A direct test in humans is almost impossible as shock waves usually are delivered to one kidney at a time but both kidneys contribute to the final urine, so changes in pH or calcium excretion would have to be compared before to after lithotripsy and be detected despite dilution of the effect by the untreated kidney.

Single kidney patients receiving shock wave treatment, or people receiving bilateral shock wave treatment could do, but the comparison would be messy: Reduced kidney function from the procedure, recent anaesthesia, changes in blood pH or bicarbonate because of reduced renal function would have to be allowed for. Most important, the comparison of before to after would require a fixed and equivalent diet, which would be difficult to obtain.

table 2 from swl paperFor these reasons we turned to an animal model: The farm pig whose kidney is much like that of a human, and likewise is similar in size.

In these animals we could shock one kidney, and then compare the treated to control side at time intervals after the treatment, the untreated side being a perfect control as both kidneys are bathed by the same blood.

Although the paper has lovely figures, I prefer this compact table that tells it all.

Urine pH was measured 61 times in the shocked and control kidneys of 9 pigs (‘basal’ column of table). The difference between the treated and control kidneys was 0.18 pH units, meaning the treatment had increased urine pH.

There was a lot more. Urine flow, and excretion of bicarbonate, potassium, chloride, sulfate, calcium, magnesium, sodium, oxalate all were higher from the treated side. This means that shock wave treatment affects reclamation of multiple molecules, presumably because of injury.

Animals were studied up to 90 days, and we could find these abnormalities throughout that time period.

You might think this would deplete the animals of all of these materials, their blood levels would fall and losses abate. But the other control kidney is normal, and can easily reduce its losses in compensation – which is what was found: the blood remained entirely normal.

The higher urine pH could have been due to two possible mechanisms: Damage to the final acidification processes in the terminal segments of the nephrons, or high delivery of bicarbonate from higher up in the nephron so that acid secreted lower down was neutralized by the bicarbonate.

To tell these apart we gave the pigs an acid load that lowered their blood bicarbonate and therefore their downstream delivery (‘Acid load’) columns. You can see the urine bicarbonate fell, and urine pH now was the same from both kidneys. Furthermore most other excess losses vanished – loss of bolding.

The tissues from the pigs showed widespread injury to tubule cells, and it was possible to integrate these changes with the altered physiology. That is too technical for this article, so I leave it to those few who wish to read the original.

The meaning of the work is clear. After shock wave treatments the treated kidney may excrete excess calcium and even oxalate, and produce a urine of higher pH than it would otherwise do. The effects are precisely those needed to produce calcium phosphate crystals. From the bladder urine, which mixes urine from both kidneys, one could never know this was happening.

It is possible that the advent of shockwave lithotripsy has contributed to the rise in calcium phosphate stones, and I hope that further science sorts out whether this hypothesis is false or true.

Incomplete Distal Renal Tubular Acidosis (dRTA)

The Background

It is one thing to say the urine pH is high in calcium phosphate stone formers and quite another to say why. Shock wave treatments can raise the urine pH on the treated side, but not the pH of the bladder urine because the normal kidney will compensate by increasing acid excretion and the pH of its urine can easily obscure the higher value on the treated side.

Yet we have the obvious high pH of bladder urine as an unmistakable trait of calcium phosphate stone formers, men and women.

One theory long popular in our field and more beloved than proven is that many CaP stone formers have a form of dRTA. dRTA is a rare genetic or acquired inability to acidify the final urine. In such patients this failure reduces acid excretion so the blood becomes unduly acid, as signified by reduced serum bicarbonate level. Potassium is often lost in excess as well. Urine citrate is invariably low, as one expects when acidosis stimulates NADC1 which reabsorbs citrate. 

Incomplete dRTA is posited as an inability of acidify the final urine not severe enough to unbalance overall acid base metabolism, so the blood remains normal yet the urine is alkaline. The hallmark of this proposed disorder is that when challenged with extra acid patients cannot, simply cannot acidify their urine as normal people do – down to a pH below 5.25 or 5, or whatever is found among the controls in a particular study. Likewise, urine citrate is to be reduced, signifying a minor but real state of systemic acid retention.

I do confess a longstanding and natural scepticism about incomplete dRTA, it being so vague and occurring as it does mainly in CaP stone formers who might well fail to acidify as a consequence of stones. Yet this scepticism has to contend with the high quality of prior work showing that acid loading fails to lower urine pH fully in some IPSF and, recently, with the outstanding work of Orson Moe and his collaborators who have brought a new and brilliant insight about the condition.

The Work of Orson Moe

Orson Moe and colleagues have performed some work I much admire and that convinces me of the reality of this borderline condition. For those of you able enough I recommend the original article which I review here only in very incomplete outline. The paper has in it an excellent review of the older literature, the one about acid loading.

With one exception, hereditary dRTA arises from gene disorders of the main proton transporters or of carbonic anhydrase itself, and these disorders are in general recessive. The recessive nature is thought to be because you need two mutant alleles to knock out the transporter whereas one good gene copy will be enough to maintain function. Heterozygotes – meaning one good and one defective gene segment – from families with dRTA tend to appear normal, a supporting fact.

The brilliance of this work is its simple question: Whereas incomplete dRTA has often been documented in the manner noted above, mainly in stone formers, if moe family with rtaone applied the same tests to heterozygote members of a family of people one of whom has complete dRTA (the real thing), are these heterozygotes really normal, or functioning marginally so that an acid challenge will disclose a weakness of acidification?

If the latter, then many people with seeming incomplete dRTA may well be heterozygotes of complete dRTA and the syndrome becomes susceptible of serious scientific analysis.

The upper part of this figure shows the altered segment of the gene for proton transport; an added CG (cytosine guanidine bases) causes a loss of an amino acid and a premature truncation so gene is too short and the protein from it is not active.

The two parents in the family tree both have a good and bad gene copy (heterozygotes). Some of the children have two bad copies and overt dRTA (Black filled symbols). The woman with the * had kidney stones without overt dRTA. There were many other heterozygotes – one normal one abnormal gene copy and one normal with two good copies to the far right.

You can see that the people with only one good gene have higher urine pH and lower urine citrate than the one with two good genes. Those with no good gene have real RTA – very high pH, no citrate.

I suspect that some CaP stone formers have their high urine pH because they are indeed heterozygotes of dRTA, some because stones and crystals have damaged their kidneys so acidification no longer works well, and some because of other hereditary factors. Whatever the cause, treatment is presently the same. You cannot safely lower urine pH; acid loads invariably cause bone mineral loss. So you have to raise urine volume, and lower urine calcium losses so as to lower CaP supersaturation. More on this at the end of the article.

How Stones Are Produced

Plaque and Plugs

We have elsewhere discussed that in our ICSF stones seem to be produced mainly as overgrowths in interstitial HA deposits, called plaque. Likewise we have shown that there are differences between our cases and those of the Mayo Clinic group (detailed in the above linked article) in that they found only some patients with abundant plaque.

We have also discussed that many other kinds of stone formers, BRSF, stone formers with bowel disease, primary hyperparathyroidism, and HASF, may have plaque and even stones forming on plaque but also have plugged terminal portions of their nephrons: Plugs of HA (mostly) fill and damage the last millimeter or so the nephron, the so called inner medullary collecting ducts and ducts of Bellini.

Plaque and tubule plugs seem to be fixed anchoring sites on the kidney papillae where stones can form and grow. Because the two articles linked above are very detailed and have lovely photos and even movies I hesitate to duplicate their materials here.

Although there is much controversy about the amounts of plaque and plugs in different stone phenotypes, there is a general agreement that plaque does form in some or most ICSF, and plugging is more or less universal among IPSF, including HASF and BRSF. There is a general agreement that over the ends of these plugs tiny stones may form and these can become of clinically important size.

Plugs and collections of small stones not rarely produce the radiological picture called nephrocalcinosis. Nephrocalcinosis can be seen in RTA, systemic stone forming diseases, notably primary hyperparathyroidism, and medullary sponge kidneys.

Distinctions Among the Three Idiopathic Calcium Stone Formers

Within the phosphate stone formers, we and Mayo Clinic have distinguished BRSF as a special case, and this specialness is perhaps most evident when we consider the presence of plaque.

Mayo Clinic has not reported their findings in BRSF with regard to plaque and plugging, but table from ha br caox comparison paperour recent publication contrasts selected laboratory and tissue findings of brushite and HA stone formers, and compares both to the far more common ICSF in an attempt to begin to clarify these three phenotypes.

Because each patient had been studied in great detail, which included intra-operative imaging of the renal papillae and papillary biopsy, numbers were small: 11 HASF, 25 BRSF (15 new to the paper and 10 prior), and 30 ICSF.

This table summarizes the main findings.

Urine pH was higher in the BRSF and HASF than in the ICSF, as was supersaturation (SS) for CaP. Urine calcium (Ca) was also higher in both CaP groups than in the ICSF. Presumably the higher pH and more marked hypercalciuria can account for the phosphate predominance in stones. But it cannot, incidentally, account for why brushite is or is not present.

Of specific interest here, about 8% and 6% of papillary surfaces were covered with plaque in ICSF and BRSF but only 0.8% among the HASF. In terms of stones, we could document an average of 10 stones/patient attached to plaque in ICSF, but only 3/25 BRSF and 6/11 HASF had stones on plaque – a 10 fold difference.

Plugging (‘deposits’ in the table) were absent in our ICSF, but were found at frequencies of 4 and 12 per cubic millimeter of tissue in BRSF and HASF. The size of deposits averaged 1.6 mm2 in BSRF but only 0.4 mm2 in HASF. BRSF formed fewer but much bigger tubule plugs.

Dilation of calyces estimated during surgery was higher in HASF than in the other two groups, and papillary injury also assessed visually higher in both phosphate groups than in ICSF.

Finally, a skilled clinical pathologist was given the cortical tissue slides from all of the patient and asked to assess them for the kinds of injury patterns found in the main line of renal diseases. Usually we do not think about kidney stones as a cause of kidney disease, but recent evidence has begun to show some possible increased risk from stones.

In this work, pathological changes in the kidney cortex which consist of either tubulointerstitial fibrosis or glomerular injury were found in only 2/30 ICSF (about what one might find in tissues from randomly selected normal people) but in 13/21 and 4/11 cases in which we had cortical tissue for BRSF and HASF. Though this is a very small sample, it does suggest that the plugging or perhaps other factors in these phosphate stone formers somehow may cause some injury higher up in the kidneys, and that may be part of the reason that epidemiological researches are finding links between stones and kidney disease.

The Idiopathic Calcium Phosphate Stone Forming Phenotype

The Faces of Janus

As Janus looked forward and backward, brushite is the first calcium phosphate phase to form in urine, and would have been expected to be the most common phase in stones. But its calcium is lightly held by phosphate and easily stolen by oxalate to make CaOx, or if not, the crystal remakes itself over time into a tighter bonded HA, which is far more insoluble and stable.

So although the first crystal, brushite is usually cannibalized into CaOx or converted into HA.

BRSF can be thought of as relics of the forward gaze of Janus.

It is HA, the later phase, which lasts, as I presume is the case in the great image of the Janus face, for what’s to come is always being taken up into the endless past. And as we can see nothing of the future, we can look back as long a way as our energy and wit permit us, for the past is eternal and always present.

The Lineaments of HASF

HASF, the greater division of IPSF is female and young in character. Tubules plug with HA crystals, sometimes admixed with CaOx, and stones grow over the open ends. Although manifest kidney disease is not obvious, and dialysis a rare consequence, one can find in biopsies some trace of renal injury not found in ICSF. Some HASF arise from ICSF whose urine pH is on the higher side. But some arise de novo, are HASF from the beginning. Some arise, perhaps, because of shock wave lithotripsy. Clinically, HA stone formers are not rarely women with nephrocalcinosis, or perhaps many stone events. They can be diagnosed as having RTA or MSK, though most of the time these less common diseases are not the cause of their stones. Actual numbers of new stones are not higher in HASF than in ICSF when adjusted for duration of stone disease. 

The Lineaments of BRSF

BRSF, the lesser division of IPSF are not sex differentiated. The reason that brushite – which should be gone – persists is unknown. Although SWL links to HA and BR stone formers, it is perhaps more prominently linked to BRSF. Why SWL should promote phosphate stones may be an increase of urine pH, as found in animal experiments. This makes, for me, some reason to desire ureteroscopy for my patients, especially now that the new instruments are so refined. BRSF have perhaps the more damaged papillae and renal cortex than HASF, so there is all the more reason to hope it’s incidence can be reduced. The clinical appearance of BRSF can be like that of HASF except it is as common in men and women, and patients often are older when they come to medical attention. The brushite stone is resistant to shock wave disruption, so that modality frequently fails to achieve a stone free kidney.

Stone Prevention

After all this detail, it seems a bit of a letdown to say that prevention of more stones is almost exactly as for ICSF.

Idiopathic hypercalciuria is a main factor along with low urine volume and low urine citrate. One cannot lower urine pH effectively, so control of urine calcium and volume are very important. SS for CaP is paramount.

One main issue is the role of potassium citrate. Trials for this agent have included calcium stone formers, some of which surely were IPSF but as minor components of uncertain amounts. Citrates will raise urine pH but citrates are potent inhibitors of crystal formation so they are of uncertain use in IPSF. We need a trial of this agent for these stone formers, and do not have one.

My practice is to raise urine volume and lower urine sodium as first steps, hoping via dilution and reduction of urine calcium excretion to reduce CaP SS by half, preferably below 1. If those goals of volume and sodium are achieved but CaP SS remains high I use thiazides. I do not use potassium citrate in IPSF because of uncertainty. My practice is of no special importance, and I give here merely as conversation, because we do not have the critical trial, so consider it for what it is worth.





  1. William Cowardin, MD

    What do you recommend for recurrent CaPhos stone formers with persistently alkaline urine and normal to high serum bicarbonate (not on diuretics, no emesis/eating issues) and no sig hypercalciuria? Another neph rec ammonium chloride. I have never given that in attempt lower urine pH on a chronic basis. In the very few patients I have had who have been tested for incomplete dRTA w NH4cL load they all had GI side effects.
    I enjoy your very informative site immensely.

    • Fredric Coe, MD

      Hi, These are a major issue. Given high serum bicarbonate and no systemic issues the high pH may come from diet peculiarities that are in the normal range. As you know well, diet contains a lot of potassium anion that is metabolized to bicarbonate, and the main sources are fruits and vegetables. Some people make smoothies or other concentrates which raise urine pH a lot. Another cause is low protein diet – check the PCR. Then, there are those in whom I have not been able to find a diet cause at all but I am not convinced by the incomplete RTA proposition – I have not written on it as yet. One reason for scepticism is that I often find high or normal urine citrate in these cases. When I am stuck with high pH I work around it. How high is CaP SS? WHatever it is I lower it with water and low sodium, the latter to bring the urine calcium down as much as I can. If the SS CaP gets below 1, stones usually become inactive whatever the pH. If that is not enough I add thiazide to the low sodium high fluid regimen. That usually is enough. I know there is no trial here, but in the meantime I get good results. Warm regards, and thanks for the question. Fred

  2. Al R.

    Hi Dr. Coe,
    Thank you so much for another extremely pertinent and valuable article! The section on Incomplete dRTA is particularly timely because I have been trying to research the known causes of innate high pH, but had found little. Also, my recent stones have been 80/20 CaOx/HA.
    As we have discussed, my baseline supersaturation test had pH of 6.8, Ca 24 of 431, Cit 24 of 570, and SS Cap of 2.01. My doctors have done a range of blood tests including NTX, a urine culture, a CT scan with contrast, and a DEXA scan and found no recognizable systemic causes, infection, or disease other than osteopenia with the characteristic osteoporosis in one vertebra – and, of course, strong IH.
    I’m hypothesizing that rather than simply IH, the ability of my kidneys to excrete acid might be somewhat impaired as a result of a genetic defect or tissue damage – and that is forcing my body to steal Ca from bones to compensate. It seems like that could potentially explain the osteopenia, hypercalciuria, high urine pH, and perhaps family history in one fell swoop.
    I had $99 genetic testing for health and ancestry info done a few years ago, but unfortunately they did not appear to sequence the gene in question. However, I have several clues: My pH seems highest in first urine when I would expect it to be the lowest as a result of normal acid purging during sleep for animal protein consumed during the day. My father and I both have had chronic issues with hypercalciuria, bone loss, and unexplained chronic tight muscles. However, my citrate seems normal at 570, not low as seems to be expected for Incomplete dRTA. And as strange as it sounds, potassium citrate seemed to elevate my Ca 24 when tried (20, and 40 mEq across three SS tests.)
    I’d really like to reach a diagnosis for a number of reasons even if that would have little impact on treatment today. But I’m concerned about the safety of an acid loading test – specifically whether that may send my Ca excretion, SS Cap, and stone risk through the roof for the three days of the test. I wonder if serum bicarbonate and pH (not yet tested) might yield some clues.

    Question – Do you have any suggestions of possible safe ways to research/test the hypothesis of an impaired ability to excrete acid? Or maybe you have a more likely hypothesis?
    Appreciate your time and anything you might offer.
    Best regards, Al

    • Fredric Coe, MD

      Hi Al, Idiopathic hypercalciuria is a cause of bone disease, and I suspect you are an example. The elevated urine pH and 20% stone CaP put you in the higher risk category for conversion to CaP stones. I would try to use very low sodium diet – 65 mEq (1500 mg) sodium daily or less, and if that does not lower urine calcium to below 200 mg and SS CaP below 1, add a thiazide type diuretic like chlorthalidone 12.5 to 25 mg daily to the low sodium diet. OF course a urine volume above 2.5 liters daily is important. Regards, Fred Coe

      • Al R.

        Hi Dr. Coe, Thank you for your reply. I have taken your hypothesis and recommendations very seriously – I would be a fool not to. Reducing sodium has worked reliably for countless thousands of stone patients.
        That said, I have been optimistically testing it very methodically. Unfortunately the data seems to consistently indicate that sodium is not my dominant factor. And logically, reducing even to zero (impossible) would not get my Ca 24 even close to 200 unless the effect were exponential. That’s a bold statement, so here’s some data from a pair of SS test showing one step of significant reduction of sodium with constant Ca intake:

        Dates: 8/27/15 and 2/22/16
        Reduced Na 24 from 173 to 125 mEq (-48 mEq = -28%) ,
        AND Added 37.5 mg Chlorthalidone and 20 mEq Potassium citrate
        AND Reduced PCR from 1.6 to 1.4
        AND Increased volume from 3.41 to 3.99 liters
        But all of these together only reduced Ca 24 from 378 to 347 (-8%). Even if we are extraordinarily generous and attribute 100% of the improvement to sodium reduction, it barely makes a dent.
        I have also tested 65 mEq sodium intake on a short term basis. And based on your recommendation I have also reduced poultry/meat by 1/3, and also reduced other protein, as well as sugar. Every little bit is worthwhile and helps, but I have only seen more small incremental improvements in the latest tests. My doctor’s opinion is that I have been eating a very healthy, balanced diet. Of course, I will continue collecting more data through the year.
        So, in light of these data, can we please expand the discussion beyond salt/protein/ thiazide? My doctor apparently only has one other patient like me, so we’re in uncharted territory. Litholink flags high pH is my single greatest risk factor in many tests. Naturally I want to learn as much about that as possible – and try to make sure it doesn’t get any worse. This leads me back to my original question (please see above.) No hurry though. This is a marathon, not a sprint, of course.
        Best regards, Al

        • Fredric Coe, MD

          Hi Al, so with reduction of urine sodium to 125 mEq/day did not reduce urine calcium. The chlorthalidone is in a high dose as 25 mg is usually enough, and that did little. Your protein intake is still very high at a PCR of 1.4 and some studies have shown quite an effect of protein on urine calcium; are you willing to lower that? The high urine pH is relevant to calcium phosphate stones – are these your variety? Ultimately all hypercalciuric conditions can be controlled, but yours is a bit pesty, I agree. Even so with all the water I would imaging supersaturations are low, and new stones will be sparse in the interim. Regards, Fred Coe

          • fredric coe

            Al, I see your comment here, not visible while editing. Your stones are CaOx with a hefty amount of phosphate so the high pH is important. I would focus on the urine calcium, however, and my suggestions are unchanged – try lowering the protein, too. PCR of 1 is good. Fred Coe

            • Al R.

              Hi Dr. Coe,
              Thx. Oh yes, I am working on PCR 1.0 with lower salt, but no data yet. I have also reduced unintentional excessive Ca intake from 1300mg/day to 1000, and Ca 24 dropped from 325 to 299. Then the interim step of reducing PCR from 1.4 to 1.2 nudged it from 299 to 291.
              I really don’t want to be a pest, yet I can’t escape the need to know more about my high pH. Based on our discussion from March on the FOOD page, I understand that animal and plant protein will have the same effect on Ca 24 for a normal person. The acid will just be excreted.
              But my pH is not normal. If my high pH, highest in 1st AM urine, were high due to a somewhat impaired ability to excrete acid, may for example, the acid cause more Ca to be stolen from my bones to neutralize it and then that Ca be excreted? O/W it seems I should favor animal over plant protein for my allotment in order to reduce my pH and CaP SS – the opposite of a normal.
              Email if easier. Best Regards, Al

              • Fredric Coe, MD

                Hi Al, the high pH is presently a research issue, and the initial manuscript is being written. It is too early to write about the matter, but we are working on it. Best, Fred

            • Al R.

              That’s very encouraging. Thank you! Your research helps so many people. Years ago all doctors had to offer my Dad was a low Ca diet – and as you would expect, the results were grim. Best Regards, Al
              P.S I found the notes on SWL in this article very interesting too even though I’ve never had it.

  3. Celia Mac Donald

    Hi Fredric, I found many different interesting things that I’d like to comment on, I’m afraid this will be long, hope you don’t mind! 🙂
    You say you put in one place all ICSF with over 50% CaOx, no cystine, uric acid or struvite (from infection). I’ve always found curious the fact that we have so few MSK members with struvite stones with bacteria and infection (only 1 that comes to mind but yet doesn’t suffer from UTIs!) yet so many with chronic UTIs and recurrent pyelonephritis and no struvite stones? (or at least their stone analysis doesn’t show struvite!).
    You say that Ca stones are more a disease of men than women! that males surpass females in younger ages but by ages 30/40 the sexs are equal. I find it curious that we only have a handful of men members (perhaps 10 out of 1000?). Could this mean they also suffer like all our members but are too shy or suspicious of FB support groups?
    About types of stones, I believe we have a predominence of CaOx stones in our MSK group.
    Referring to CaP% stones and Lithotripsy; most of our members have had inumerable ESWL procedures for stones including my sister who was initially diagnosed with CaOx stones then at some point her stones turned to CaP.
    Reference to mechanisms in Phosphate stone formation; urine suppersaturation of CaP depends on urine volume, calcium excretion, phosphate excretion, low urine citrate, high urine pH: many of our members have these same conditions!
    Regarding “Physiology Post SW Kidneys” interesting the fact that all levels increased including urine pH after ESWL and that this procedure is known to affect reclamation due to tubule cell injury! (which could cause inflammation and trigger crystalization and calcifications?)
    Referring to High bladder urine pH a trait in CaP stone formers; I wonder if this high pH could have anything to do with IC which so many of our MSK members suffer from?
    Referring to dRTA, I believe we could have many members who suffer from this form of RTA although they have been only been diagnosed with generic RTA and no definition. Most members have low citrate, low potassium. Concerning the hereditary form of dRTA due to gene disorders, I believe many could have this form but majority of nephrologists treating MSK don’t do gene testing for a proper diagnosis? Including my sister’s, I wonder why?
    I find it interesting that you suspect some CaP SF have high pH due to Heterozygotes dRTA, some due to crystals damaging kidneys AND that urine pH cannot be safely lowered because “acid loads” cause bone disease! the same bone disease already known to be caused by MSK as well. But you say “whatever the cause” the treatment remains the same “increase urine volume and lower urine calcium loss”!
    Referring to the difference in plaque and nephrocalcinosis, I’ll have to get back to this topic!
    Thank you so much for listening and appreciate your patience, I’m trying so hard to understand!

    • Fredric Coe, MD

      Dear Celia, You certainly are my most careful reader. Many shock wave treatments do indeed associate with phosphate stones, and I suspect may raise urine pH and actually cause conversion from oxalate to phosphate stones. With modern ureteroscopes the use of SWL will no doubt wane. I think the high urine pH of phosphate stone formers is from their kidneys as it is in the kidneys we find the high phosphate stones – very often. And, it is the kidneys whose tubules are plugged with phosphate crystals. Finally I think many of your members have calcium phosphate stones and that is why they often report the findings you note above. Even so, prevention is very successful, and worthwhile for them. Warmest Regards, Fred

  4. Celia Grace MacDonald

    Hi Fredric, I’m just getting to this article now. One thing I did note though at first brouse, is where you stress that duct pluggings are made of calcium phosphates, apatite and/or brushite. From what I’ve read Randall’s plaque or nephrocalcinosis is also made of hydroxyapatite, on top of which CaOx stones may form depending on whether a patient suffers from hyperoxaluria, my sister Laura does not.
    Just one question for now, in your opinion, what do you think MSK tubule ductal stones are made of? If not calcium phospates (apatite/brushite)? I’ll be back! Thank you.

    • Fredric Coe, MD

      Hi Celia, Duct plugs all seem to be made almost completely of apatite, with brushite or calcium oxalate growing on them. A few have traces of brushite or CaOx in the plug itself, but mostly these are growing over the open end of the plug where they make new stones. MSK ductal stones are calcium oxalate and very different from plugs. They are very tiny round stones, like microscopic BBs, they do not attach to the walls of the ducts the way apatite plugs do, and they do not harm the lining cells whereas plugs destroy the lining cells. There is no inflammation around the MSK ducts. In general MSK patients form calcium oxalate stones, and have few if any tubule plugs. Warmest regards, Fred


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