The large picture shows a papillum of a patient with ileostomy as seen at surgery for stone removal. The large white patch between the arrows is plaque, the stuff calcium oxalate stones can anchor to and grow on. The yellow material between arrowheads is terminal ducts of Bellini (BD) plugged with crystals. Both are abundant in patients with ileostomy and part of how they form stones.

This article relies on only three research publications, and in all modesty I must admit they arose from our research group. But in defense, one is remarkably comprehensive and one the only one with detailed study of kidney tissue obtained during stone surgery. Also in defense, their reference lists are good enough to give anyone access to other related papers. Finally, apart from the kidney tissue, our work is in line with what everyone else has found, so in using it I am presenting a main consensus.

How Ileostomy Promotes Stones

Water and Electrolyte Loss

The colon reabsorbs large amounts of water, sodium, bicarbonate, calcium, and potassium. When colon is lost from surgery for cancer or inflammatory bowel disease, what it once reabsorbed is also lost into ileostomy drainage. Kidneys compensate as expected, by producing a scanty and acidic urine low in sodium, calcium and potassium. Kidney cells conserve filtered citrate and metabolize it to bicarbonate to help make up for ileostomy losses. Likewise, they produce copious ammonia, a way of removing acid from the body.

All these compensations supersaturate the urine with respect to calcium oxalate – low volume, and uric acid – low volume and pH. As a result, calcium oxalate and uric acid stones occur.

Does Not Increase Urine Oxalate Excretion

Much the same pattern of water and electrolyte loss occur after loss of small bowel from surgery or other cause. Losses are less severe when the colon remains in place because it can reabsorb some of what escapes from the small bowel. But the colon is affected in such a way that it permits abnormal amounts of oxalate to pass through its linings into the blood. As a result urine is high in oxalate as well as scanty and acidic – so called enteric hyperoxaluria. 

Dehydration vs. Oxalate

This is a key point of distinction. Ileostomy causes stones and poses serious risk of kidney injury from dehydration. Small bowel resection poses less risk from dehydration but more from excess oxalate excretion that can cause both stones and severe kidney injury. Ileostomy plus small bowel resection, therefore, causes extreme risk of dehydration, but loss of colon removes the source of extra oxalate. In other words, with or without associated small bowel disease, patients with ileostomy form stones because of electrolyte and water loss, not excess oxalate.

Supersaturations

In our past and recent publications we have found people with ileostomy mainly form uric acid and calcium oxalate stones. The papers referenced in the bibliographies of these two papers describe about the same proportions of stone types. One should expect that urine supersaturations will be high for both crystals. Moreover, given that ileostomy leads to scanty acidic urine we should find that supersaturations arise from low urine volume and pH.

Urine Volume

The importance of urine volume is easy to demonstrate using our own data from 7 patients with ileostomy whom we studied in considerable detail.

In the figure, SS for uric acid is in red circles, that for CaOx in blue. Both rise as urine volume falls. The vertical line at the right marks the volume at which Curhan found overall population stone risk was reduced to baseline. Four points lie on or to the right of this line.

In our cases that volume of 2.3 l/d seemed to confer only marginal safety. I say this because risk of uric acid crystallization begins as soon as supersaturation rises above 1 (lower horizontal dashed line) and one of two uric acid points lie above 1. Similarly, one CaOx SS lies below the point at which these crystals usually form but the other is much higher.

So, one should raise urine volume as much as possible and try to reach above 2 liters/d. But that may not be enough in all patients, so 24 hour urine testing is always required.

Uric Acid SS

Urine pH

An obvious reason one needs such urine testing is to ascertain 24 hour average urine pH. In the main article on this site concerning uric acid stones, I offered evidence that urine pH is the main factor controlling uric acid supersaturation, and that is the same for ileostomy patients.

In the 3D figure to the right, uric acid SS is on the vertical axis. SIx of the SS points lie above 1, as on the graph just above, and one is below 1. This last had the largest urine volume (size of the symbol), among the highest urine pH, and lowest 24 hour urine uric acid excretion rate.

Uric Acid Excretion

The graph shows little correlation between the 24 hour urine uric acid excretion rate and uric acid SS, That is because urine pH is so powerful a determinant of SS. The two patients with very low 24 hour urine uric acid excretion (values at or below 200 mg/d) undoubtably crystallized uric acid either in the collection container or in themselves, as these values are below any expected from an adult. 

Calcium Oxalate SS

Urine Calcium

In general the lowest SS CaOx was in the patients with very low urine calcium (below 100 mg), but in fact all but one patient had a urine calcium excretion below 200 mg, the level at which Curhan first documents elevated stone risk in a general population. The one patient with very high urine calcium had very high supersaturation despite high urine volume

Urine Oxalate

As others have found, and we in a larger patient series, urine oxalate was not remarkably high in our patients – size of symbols. Moreover, urine oxalate had little correlation with supersaturation.

Urine Volume

As I have already shown, but in isolation, supersaturation was generally higher in the patients with low urine volume, with the exception of the one person with exceedingly high urine calcium.

Confirmation in a Larger Series

I have illustrated only the 7 cases we biopsied in order to demonstrate the tissue changes in ileostomy, but in all fairness I should show that the pattern among the seven is the same as that in our larger series of more routine cases that never were biopsied.

In this much larger series, ileostomy cases (I) are compared to those with small bowel resection and ileostomy (SB+I), with small bowel resection but retained colon (SB), with no surgery but bowel disease (NONE) and stone formers with no bowel disease at all (SF).

Urine volume and pH (upper two panels) of ileostomy patients are lower than any of the other groups. Of interest, urine oxalate (lower left panel) is also lower – presumably as colon is absent. Urine calcium (lower right panel) is not as remarkably divergent except as against stone formers without bowel disease. It is the ileostomy patients who also have small bowel resection who display remarkably low urine calcium having lost main areas for calcium absorption.

How Stones Form

Growth on Plaque and Plugs

Stones form in the common ways we have found across a spectrum of stone diseases, as overgrowths on plaque or on tubule plugs.

The upper left panel shows a papillum from a patient during stone surgery. The dark blob is a large crystal plug. The little inset shows a biopsy of this area scanned in a research high resolution CT instrument. The arrow points to the crystal deposit in the biopsied tissue.

All seven of our biopsy cases had plugs, between 1 and 26 plugs/mm³ of biopsy tissue. At the highest level, tissue is significantly replaced by plugs. The upper right panel shows a plug protruding from the opening of a tubule (at the arrowhead).

Panel C at the lower left shows a stone (double white arrows) growing over white plaque. The attachment site on the removed stone is the white region in panel d marked out by arrowheads. All stones that grow on plaque have these attachment sites that are always calcium phosphate (hydroxyapatite) even when the stone itself is calcium oxalate.

This stone was no exception. A micro – CT analysis of the stone shows mainly calcium oxalate – the iron grey mass. The attachment site (arrowheads) was hydroxyapatite, as expected.

So in a way ileostomy offers no surprises. Dehydration raises supersaturation, plaque forms, tubules plug, and calcium oxalate stones grow in the common way. Alkali loss lowers urine pH, and uric acid crystallizes forming stones.

Uric Acid Stones were Not attached

Growth on plaque or plugs applies to calcium stones. Uric acid stones were never found attached to plugs or to plaque. They were free in the urinary system. We presume that because urine contains a lot of uric acid compared to oxalate, and because uric acid can crystallize rapidly when urine pH is low, crystals form and somehow manage to stay in the kidneys long enough to form stones rather than be washed away in the urine.

Tissue Damage

One might expect that tubule plugs damage the papillae and in fact they do.

The upper left panel labeled a shows minimal damage in one of the seven patients we biopsied. Panel b just next to it, shows a ring of plugs. A higher power view in c shows how the lining cells of the tubules are gone – damaged and lost, and around the tubules with plugs the tissue looks condensed because scarred. In panel D the arrowheads point to plaque growing as tiny beads in thin limbs of the loops of Henle, and a plug at the tip of the arrow.

Not shown here, a few collecting ducts were plugged in the renal cortex – the region that contains the glomerulae and is very sensitive to crystal injury. Cortex crystals are rare in common stone formers.

What Plugs Were Made Of

I have shown you how acid the urine is in ileostomy and for the obvious and well known reason that ileostomy fluid is alkaline because enriched with bicarbonate the colon would have absorbed back into the blood. The urine pH is low enough to produce uric acid stones, geological proof that low pH is common and enduring.

What, then, would you predict the plugs were made of?

I would have said uric acid, of course. But in fact that was wrong.

Plugs Were Calcium Phosphate

Many plugs stained with the Yasue stain meaning they contained calcium. Using high resolution IR scanning we found the crystal was hydroxyapatite – as in almost all other plugs studied to date.

But why?

The urine produced in these tubules is very acid, acid enough to produce uric acid stones, and stones themselves are calcium oxalate – indifferent to urine acidity or alkalinity, and uric acid. None have appreciable apatite.

All of the urine in a 24 hour urine collection comes out of the terminal collecting ducts of Bellini (BD). There is no other pathway out of the kidneys. That urine is acid and only one of our patients had any supersaturation for calcium phosphate – the other 6 produced a urine undersaturated for that crystal so it would dissolve. How, then, did apatite forms of calcium phosphate come to predominate in those very same tubules?

We guessed that somehow plugging began with uric acid, or even possibly calcium oxalate, cells were damaged, and local pH in the damaged tubules rose way above that of the bulk urine so whatever crystal began the deposit would dissolve in favor of calcium phosphate. Given that calcium oxalate will not dissolve if pH rises, this leaves uric acid as the main possibility.

Some Plugs Were  Urate

Urate sounds like uric acid but is not. It is the salt of the urate ion with sodium or ammonium, in these cases, whereas uric acid is not a salt but the pure molecule essentially crystallizing with itself. These two urate salts were found in some plugs, as regions that did not stain with Yasue stain nor contain apatite when scanned by IR.

How Could Urates Form?

These two urate salts can exists at higher pH levels than uric acid, so they could coexist with apatite. But how either formed, urate salts or apatite, remains a mystery. Before crystals forms, these ducts produced a fluid too acid for urate or apatite. After crystals formed, damage from crystals could have raised fluid pH and permitted urate and apatite to form. The only crystals that could form at the low urine pH of ileostomy patients are calcium oxalate and uric acid.

The Uric Acid Theory

Obviously that leaves uric acid, and one asks if any uric acid was in plugs.

Unfortunately, the IR technique we used to identify the urate crystals and apatite crystals cannot identify uric acid itself. Uric acid produces no unique infrared bands as a signature. This leaves untested the theory that plugs begin as uric acid, damage tubules so pH rises, and uric acid converts to the two urate salts. It is a powerful theory because if true it means that consistent alkali treatment to prevent uric acid could prevent plugs and tissue injury but after tubules lose acidification because of injury alkali cannot undo the injury process.

The Calcium Oxalate Theory

Urine and therefore tubule fluid was supersaturated with respect to calcium oxalate, and surely this crystal was abundant in stones. Why not imagine it formed first, damaged tubule cells, and dissolved in favor of urates and apatites?

It is less likely than the uric acid theory.

To date calcium oxalate has been rare in human plugs, seen only in obesity bypass patients and primary hyperoxaluria, states of marked oxalate over excretion. Urine oxalate tends to be low in ileostomy patients and CaOx SS was not remarkably high compared to common stone formers whose plugs never contain calcium oxalate.

Dissolution of calcium oxalate is not very likely. It is a very insoluble phase, and conversion of calcium oxalate to apatite or uric acid has not been demonstrated very often even in vitro. More, the IR technique we used easily detects calcium oxalate, so even traces were absent in these patients.

So while possible, the calcium oxalate theory takes second place to the uric acid theory. Wanting is a method for micro-analysis of tissue plugs that can detect uric acid in the presence of urates.

Apatite and Urate Deposit Locations

Sometimes the apatite and urate deposits were together in one tubule, but more commonly they were separate. Those that did not stain with Yasue – no calcium – tended to locate in terminal collecting – Bellini ducts, whereas those with calcium were higher up, in the inner medullary collecting ducts. Moreover, tissue around ducts plugged with urates showed more inflammation, and tubules more signs of injury as compared with tubules plugged with calcium – apatite – crystals.

What Do We Say to Patients and their Physicians?

The problem of ileostomy stones is loss of alkaline fluid from the intestines. Kidneys adapt properly and form an acidic scanty urine.

Treatment Priorities

The low pH may well be of most primary concern because of plugging as an irreversible outcome from an initial uric acid deposit, so alkali treatment should be early and consistent with a goal of urine pH about 6. Because ileostomy causes sodium losses, sodium alkali may be useful; here 24 hour urines will be very valuable as a guide.

Urine volume is the other critical factor. WIthout any trial justification, I have come to favor glucose containing beverages. Sodium coupled glucose transport in the jejunum may improve absorption so fluid intake does more than increase ileostomy output. Usually, I have been able to achieve increases in 24 hour urine volume, often to 2 liters or more. But doing this is highly individual to each patient and physician.

High urine oxalate, often thought of in bowel disease related stones, is rarely an important factor given ileostomy. Likewise, urine calcium usually is not high. Nevertheless both need to be looked for and treated if present.

Testing as a Priority

Serum and 24 Hour Urines

This entire set of comments points out the critical role of 24 hour urine testing for sodium, calcium, oxalate, pH, volume – all of the factors used in evaluating stone formation. They are needed to plan treatment and monitor its course.

Ileostomy can cause acute and chronic kidney damage, and also cause metabolic acidosis or alkalosis, so serum measurements need to be perhaps more frequent than 24 hour urine collections. Kidney failure risk is particularly well documented in the period immediately and one year after ileostomy.

Kidney Stone Analysis

Likewise all kidney stones need be analysed to help assess the relative concern over calcium vs. uric acid stones. Even though 24 hour urine testing gives insight into stone cause, stones give insights into the actual urine supersaturations over a longer term average.

Timing of Treatment

Although I am perhaps speaking a bit out of line in terms of clinical practice, I certainly do begin alkali treatment after even one stone in a patient with ileostomy and not wait for another. This is because plugging is damaging and may progress without evident new stones for a time.

One might even question if prophylactic alkali were not unreasonable in anyone with an ileostomy. Lacking any trial data, I am of two minds. Sodium depletion is so common, and sodium alkali so relatively inexpensive – some sodium bicarbonate tablets might do – the benefits could easily outweigh any risk and cost. I do not indeed see non stone forming ileostomy patients, however, and therefore have no experience in this matter. Individual physicians can determine the issue on a case by case basis.

But immediately after ileostomy, acute kidney injury is specially frequent, and given low urine volume and pH are very likely uric acid crystallization is as well. One might want to use sodium alkali especially during this period. A trial might be of high importance for this matter.