The magnificent painting (oil on oak panel) by Hieronymus Bosch (“The Extraction of the Stone of Madness“), was created between 1501-1505), dwells in the Museo del Prado since 1839, and has a provenance unbroken from its first owner, Philip of Burgundy, Bishop of Utrecht. We chose it because brushite stones are maddening, to everyone. For patients, remarkably fast growing. For surgeons, numerous, and often large and hard. For physicians, difficult to prevent. For those who study stone disease, a kind of stone that should not exist at all – an enigma.

Elsewhere on this site one of us wrote about the brushite crystal. It is simply calcium and phosphate ions, in equal portion, loosely combined in a lattice that also contains several water molecules. As such brushite forms readily and is more soluble than the usually more durable calcium oxalate and hydroxyapatite crystals that make up most of the common calcium stones.

Among the first to form in human urine when supersaturation is raised, brushite is fragile, or, better said, prey to other urine crystals. Given any urine saturation with calcium oxalate, oxalate ion will literally pull the surface calcium off of the brushite surface, cannibalizing it to make more calcium oxalate. The same for hydroxyapatite, which forms on brushite surfaces and ‘eats it up’. The above article reviews the complex and undeniable experiments that demonstrate all this. So how does brushite survive in certain patients? Not only survive but produce among the more aggressive and persistent stone conditions?

In fairness we should admit that we do not know and believe no one does. But patients form these stones, physicians work to  remove and prevent them, and all should want to know what is known so as to best minimize recurrence and kidney damage. That is why we wrote this article despite serious gaps in our scientific knowledge.

SOME PRELIMINARIES

By ‘brushite stone formers’, we mean patients with any brushite in any stone.  This rather Manichean approach is reasonable because in general ‘any’ bruthite usually means a lot of brushite, either now or to come.

We will use a lot names here and need abbreviations: Calcium oxalate (CaOx); hydroxyapatite (HA), the form of calcium phosphate (CaP) crystals common in stones; brushite (Br); stone formers (SF). Because Br SF usually do not have a systemic disease driving their stone formation, they are a subtype of idiopathic calcium stone former (ICSF).

CLINICAL BRUSHITE STONE DISEASE

Medical and Impressionistic View

Let’s look at how brushite stone formers appear to those of us who practice stone prevention. Although men are a higher fraction of Br SF, CaP SF are far more often women than men, so one encounters the disease more often in a woman. The story is of many stones, often more in one kidney than the other, that recur and grow rapidly, often over months – faster and larger than in the routine CaP SF. Because hard, Br stones do not fragment easily with lithotripsy. Pain not associated with stone passage seems common, although we do not have a reference for this observation. Because of large and multiple stones, and many surgeries, the renal papillae are often abnormal with tissue damage. Br stones can form in one of two kidneys while the other forms HA or CaOx stones, for uncertain reasons. There is a hint in published studies that Br stones may be more common in kidneys with abnormal drainage.

Everyone, patients, family, physicians recognize this disease is mean spirited and deserves the highest efforts at stone prevention. Those of us experienced in such prevention know it can be very difficult to achieve.

Scholarly Details

We and others have found hypercalciuria is very common in Br SF but much the same may be said for all CaP stones. Fuster and his colleagues have noted that low serum phosphate is perhaps a bit more common in Br than other CaP SF. Urine from all CaP stone formers is more alkaline than CaOx SF, generally pH 6.2 – 6.3 vs 5.9, and urine citrate is lower.

In common with other CaP stone formers, those with Br stones lose an abnormal amount of ammonia in their urine which, along with their low citrate points toward some intrinsic disorder of proximal tubule cell acid sensing. The low citrate is a general stone risk factor, for all stone types. It has been specifically identified as a risk factor for brushite stones. 

We found a strong association between numbers of shock wave lithotripsy procedures and the fraction of phosphate in kidney stones. Krambeck and her colleagues have reported the same but specifically for Br. Using pigs, we were able to show that SWL of one kidney caused a widespread disorder of thick ascending limb function that released abnormal amounts of bicarbonate into the urine raising pH. Possibly this might be the physiological link between the SWL and CaP/ Br stones.

As we shall detail a bit further on, the papillae of brushite stone formers display considerable injury. But specifically the tissues are inflamed more than is common in stone disease. Unlike the pattern found in CaOx and routine CaP SF, one finds neutrophils, the white blood cells recruited to sites of infection or other acute injury. Moreover the neutrophils are ‘activated’, extruding their interior proteins as if to contain a bacterial invader. The urine of Br SF contains more leukocyte enzyme (esterase) than among other stone formers, perhaps a reflection of their specific inflammation and also possibly a useful clinical tool.

INSIDE THE KIDNEYS

The Patients Whose Kidneys We Looked Into

Among the earliest detailed descriptions of brushite disease is our own, which we believe illustrates things well. We described only 10 cases but for each we had papillary and cortical kidney biopsy tissue obtained during stone surgery. Such tissue studies are crucial for understanding stone disease, and each case a massive effort. Among the 10, 5 were men. The ten patients indeed had a lot of SWL procedures (1-11) and all but one more than the usual number of stones (9 – >30). Their average age at biopsy was in the mid 40’s.

It is said that urine calcium is higher in Br vs CaOx SF. Indeed we found 95% confidence intervals (CI) of 295 – 269 mg/d vs CaOx patients of 242 – 258, males, and 183 – 273 vs 190 – 216, females, respectively. Because the 95% CI of Br SF does not overlay that for CaOx SF males, one can say their urine calcium excretion was higher; thus we bolded it. For women, there was overlap, so we cannot say there was a difference.

One can apply the same comparison methods for other measurements. For urine citrate, also mg/d, male Br SF excreted 407 – 578 mg/d vs. 521 – 569 for CaOx SF – overlap. Among females values were 264 – 494 vs 476 – 558, Br vs CaOx SF, also overlap. Urine pH was indeed higher in males and females among Br SF vs. CaOx SF: Males 6.2-6.4 vs 5.9-6.02; females 6.1-6.4 vs 5.9-6.05. But this is not unique to Br but generally true for all CaP SF. 

In effect, urine stone risk factors, in this highly select and therefore small series of patients, did not differentiate brushite patients from calcium oxalate stone formers studied in the same way apart from urine pH. The latter trait does not differ from that of routine HA CaP SF.

The Crystals in Kidneys

Plugging

This is one renal papillum viewed through an endoscope during stone surgery in a Br SF. We have shown this dramatic picture before in a general review of plugging. Why again? Because plugs in Br SF are much larger than in the other stone diseases and this is a very fine illustration of that fact.

At the ‘*’ you are looking at a mass of crystals filling the opening of a duct of Bellini (BD) – the terminal end of the nephrons where the final urine leaves kidney tissue. Each papillum has perhaps a dozen or so BD, giving 100 – 200 in all for a kidney. Since a kidney has about one million nephrons this means each BD drains about 5,000 to 10,000 nephrons. With such a damaging blockade of a BD one should expect some evidence of nephron loss higher up in the kidney cortex, which I will show you a bit later on. The arrowheads show a pitting deformity of this papillum, and the single arrow some white plaque. Stone can grow on such plaque, a fact widely reviewed on the site. 

A similar plugged BD is in another tissue biopsy. The plug runs through the plane of the paper, so you are looking at its cross section. The crystals are stained black. The * and line point to protruding crystals from a different duct. The arrows call attention to the absence of lining cells – all we have of what was once a tube made of living cells is a crystal shell.

We could proliferate these illustrations with more examples, but it would be of no value. The message is here: Brushite stone disease consists in a modest number of very large and destructive plugs at the ends of the BD which are the terminal points for the million or so nephrons. Crystals can grow over these ducts and break off to become stones. I should add, in passing, that plugging can extend up even higher in the nephron to include the BD and the inner medullary collecting ducts. The higher it goes the more the damage crystals can produce.

One might surmise that the plugs were made of brushite. That is, after all what makes this group of patients different from all other CaP stone formers. But no, the plugs are mainly HA, the same crystal that makes up the bulk of plugs in all forms of stone disease. More about the plugs themselves a bit later on.

Plaque and Plugs Together: Comparing Br to HA CaP stone formers

Although a most dramatic feature, large plugs are not alone as a basis for stones in brushite stone formers. They also have considerable plaque.

This synthesis of a larger number of patients shows Br SF as circles, and routine (HA) CaP SF as triangles. Filled or not is not relevant here.

On the left we plot the size of deposits vertically, in mm, against their number /mm³ of tissue scanned – horizontally. The CaP SF span a wide range of number from 1 to 40 (mean = 12) whereas Br SF numbers are much smaller (1 – 8, mean =6). But though fewer in number, BrSF have an average deposit size of about 1.6 mm, vs. 0.6 for CaP SF, a nearly 3 fold difference.

For plaque, look at the right panel, horizontal axis. In CaP SF plaque covers on average about 0.8 % of papillary surface vs. 6% in Br Sf. So Br SF have considerably more plaque surface for stones to form on. We will show a bit later on that even so they seem to produce very few stones on plaque. That is yet another oddness, because CaOx SF form many stones on plaque yet have an average coverage not greatly higher – about 10%.

TISSUE INJURY IN THE CORTEX

In many patients we studied, we took samples not only from the ends of the nephrons, where stones form, but from the nephron beginnings where filtration takes place – the renal cortex. Given the damaging effects of the large plugs and that each plugged BD drains many nephrons, each with its own glomerular filter, one might expect more damage in the cortex than in other forms of stone disease.

In fact, that is true. The brushite (filled circles), HA (open circles) and CaOx SF (black triangles) are arranged along the horizontal axis in terms of the amount of tubule loss and scarring in the renal cortex. The amount of glomerular damage is displayed vertically.

CaOx SF (black triangles) have no significant cortical disease. Some CaP SF (open circles) and many Br SF (filled circles) have disease in the cortex. Br SF have the worst disease (upward and to the right filled circles).

Do not expect this will show up using the routine measurements of clinical practice. Even when significant numbers of nephron units are destroyed, those remaining can increase their filtration so things seem normal. But such ‘hyperfiltration’ or perhaps better phrased ‘compensatory hypertrophy’ may not be ideal in the long term. Pressures and flows must rise in filtering capillaries, with risk of later life damage. This topic is not within the purview of this article.

OFTEN BRUSHITE STONES ARE ADMIXED

Among Stones

We said at the beginning brushite in any amount in any stone defines a ‘brushite’ stone former. If we look at the set of patients from which we selected the last 2 figures, brushite was almost never the sole crystal in the analyzed stones (points lying on the horizontal axis). Usually CaOx or HA was admixed. Furthermore, there is no special pattern of one or the other the predominant companion to Br.

The points are jittered so they do not overlap. For this reason brushite values of 0 spread below and above 0. The four points just above 20% brushite are the first above 0. The presence of 0 brushite stones is simply to say that not all stones of Br SF contain Br.

Over Time

In this series, when CaOx was the final stone analysed none preceding contained Br. On the other hand, when Br was in the first stone the last stones never contained CaOx. This slim set of facts suggests a larger principle at work. It may be that BR in stones is a kind of end point from which a kidney does not return to CaOx stone production. We consider this remark pure conjecture but interesting.

Between Kidneys

In 5 of the 26 patients we had multiple stones removed surgically from both kidneys and found in all 5 that one kidney was producing Br containing stones while the other was producing CaOx or HA stones with no Br. This points to the importance of local factors such as infection, or damage from stones or surgery, or perhaps urological drainage abnormalities as important in producing Br in stones. It also seems kin to the prior observation of a sequence: CaOx, then Br, seemingly never Br then CaOx.

HOW BRUSHITE STONES FORM

Given all this, what do we know about how brushite stones are produced. In other words are they produced on the plugs, on plaque, or perhaps within the final urine itself?

We have identified formation site for 38 brushite stone formers. Of them, 23 had stones free in the urinary system whose site of origin could not be determined. fourteen formed at least one stone on a plug. Two who formed a stone on a plug also formed a stone on plaque. Only one patient formed a stone only on plaque.

On Plugs

Here is a stone on a papullum during removal with a basket (thin wires around it). The wires surround the connection between it and the surface of the kidney. You can see it is attached and one will have to pull it off.

Here is the very same stone. It is visualized using a micro-CT that can image the crystals and from the image let us know their composition. At the bottom of the picture is the plug, which is made of hydroxyapatite (label). So what you see in the surgical image is a stone growing on the open end of an apatite plug within a Bellini duct.

The plug is about 1 mm wide, as you can tell from the 0.5 mm measure line at the lower right. One mm is very large compared with the diameter of a normal Bellini duct. The largest apatite plugs in routine CaP stone formers is barely 1 mm and the average is 0.6 mm. Look back four figures (we know its a long way and this article is exhausting) at the graphs we showed of plug dimensions.

Over the apatite plug a layer of calcium oxalate grew from urine ions: The exposed surface of the apatite plug organized the urine ions of calcium and oxalate into a CaOx crystal overgrowth. So far this is nothing rare. We have many examples of CaOx stones growing over apatite plugs. We will put up an article about this soon. But right now just believe it or read the linked article that shows the original data.

Probably because the urine has a rather high pH of about 6.2 – 6.4 in brushite patients, a layer of hydroxyapatite came next, over the CaOx. This kind of overgrowth is commonplace in mixed CaOx /HA stones.

But the next layer is what we came for – there they are, brushite crystals, topping the stones like a flourish of chocolate icing over a cupcake.

This cupcake image seems to be apt, in that a survey of stones and plugs from brushite stone formers showed brushite as a kind of topping, forming as a last layer, usually (87% of the time) over CaOx.

More Cupcakes with Brushite Frosting

Rather than words, here are three examples from the paper linked just above. They make the point for us. Apatite plugs form and CaOx generally layers over it. Brushite comes like frosting, but as in the case of small cupcakes the frosting makes up the bulk of the product.

 

 

 

On Plaque

One might assume this process of successive layering would occur frequently over plaque. Plaque is abundant in kidneys of patients who form brushite stones, and the process of overgrowth – calcium phosphate initial layers, CaOx next – should proceed apace.

But no. Only 3 of our 38 cases so far formed a stone on plaque. Two of these 3 also formed stones on plugs. Dr James Lingeman (personal conversation 6/6/24) remarks that in his long experience stones on plaque are uncommon during surgery in brushite stone formers.

The picture below depicts a CaOx stone from the a patient in our series of 38 patients who formed a stone on plaque and also produced brushite stones in the same kidney.

How odd, you think. Why not more on plaque?

We do not know.

A kind of deep fog overlays the brushite kidney and we have not as yet found our way. So much plaque and more or less almost no stones form on it.

What Grows Where?

We have shown you a glimpse of plugs, a stone, but what about the whole parade of 38 patients?

How about a count me up of what grew where and on what so we get an overview of what to expect?

To do this took two of us. Jim went back for each case and determined if a stone formed free, on plugs, on plaque or a patient had both. The counts are in the left hand panel of this figure.

How we counted here is crucial. If even one stone was clearly formed on a plug the patient was classed as ‘plug’ and the same for plaque and both. So the counts are of patients, not of the mass of stones they produced.

Most patients formed stones that were found free in the urine without evidence of plug attachment. The other large fraction formed stones with evidence of plug remains or actually growing on a plug. One formed stones on plaque – the one we showed. Two patients had stones both from plaque and plugs. So the 38 patients mainly formed stones seemingly free in the urinary space or on plugs. It would be easy to miss the signs of a plug in stone fragments so these are very approximate counts, and plug origin is more likely to be undercounted than over counted.

Among the patients with only free stones (Right panel) a majority were just brushite (B). Small fractions of the stones were brushite growing over CaOx (CB) or over HA (AB). This means there was no evidence of a plug but there was admixture within the stone of brushite with the other crystal(s) and they were intertwined meaning growth one over the other. Note that the vertical axis shows the fraction of all patients in a group that had a specific pattern of stone growth. For example the one patient with a stone on plaque had 100% (1.0 fraction) of all stones on plaque. Fractions may total up over 100% because some cases are counts from both kidneys.

Among patients with stones growing on plugs or carrying plug residues, quite a few stones showed brushite over HA (AB) and a minor fraction growing over CaOx. Being rare, we cannot make much of the counts from patients with stones on plaque or both plaque and plugs.

The message here is a majority of Br SF had stones free in the urinary space. Whether the original plug was lost or on fragments not fully analysed is not knowable so plug stones can be easily underestimated. Plaque seems a very unusual place for Br SF to produce stones. In patients who formed stones on plugs, stones are more often found on HA or CaOx than brushite alone.

WHAT IS BRUSHITE STONE DISEASE?

Peculiar, certainly. Underneath the disease we seem to have the commonplace mechanism of apatite plugging with urinary crystal overgrowth – often calcium oxalate. This usually creates nothing more than one form – the plugging form – of idiopathic calcium oxalate stone forming.

But here, brushite somehow manages to overgrow, usually over calcium oxalate crystals, and make the stone a lot larger. Being a rapidly forming crystal in human urine, brushite can then lead to what we see clinically – a large stone mass, quickly growing.

So mysterious this seeming nuance, so important for patients. Usually brushite forms as an initial phase in urine, and is cannibalized by oxalate or apatite, so we do not see it.  But here it is somehow enabled, become stable, prominent.

How? We have no idea but can imagine possibilities we mention at the very end.

WHAT TO DO?

Clinical Care

No trials, no security. We must reason as best we can and offer some thoughts to physicians and their patients. Brushite stone disease does not seem to begin with brushite so much as eventuate from the rather common plugging form of CaOx stone disease, and, perhaps, from routine CaP stone disease. Once in process, then, what we must aim for is to reduce or stop the underlying plugging and CaOx overgrowth. In other words treatment is not different from the usual except we need to proceed with as much vigor as possible.

That means to reduce CaOx and CaP SS as far as possible, as soon as possible, and as stably as possible. We have no means to prevent what appears to be an overgrowth of brushite over CaOx or HA, just as we have no idea as to why it happens in this rather select group of patients.

Research

If indeed we are not wrong, and brushite stone disease is an extension of the common plugging forms of CaOx stone disease, or of otherwise routine CaP stone disease, if indeed it is such an extension, we need to understand how that happens. I have detailed elsewhere how brushite is easy prey to CaOx and HA crystals, yet here, in these patients, it seems to have staying power. The most simple explanation is something in the urine stabilizes it – the brushite -, yet allows it to grow rapidly.

One possible cause is the neutrophils. They extrude there proteins into the urine in this one condition, and those proteins are evolved to stick to and engulf bacteria. Possibly they stabilize brushite. Often, a coating macromolecule will permit overgrowth, resulting in layers of crystal, organic materials, and more mineral. One should be able to detect neutrophil proteins within Br coatings, if this idea is at all reasonable.

Why neutrophils?

The more common inflammation we have documented in stone formers involves T cells and macrophages. Among uric acid stone formers an elevated ratio of blood neutrophils to lymphocytes seems correlated with progression of chronic kidney disease, suggesting some link between their presence (here, in blood) and renal damage, but that is very far from our situation here. Somehow the neutrophils arouse our suspicion as actors in this odd condition.