How kidney stones form surely offers clues to how to prevent them. But they hide those clues very well.
We cannot watch them form, as in a movie. It would take too long and we have no cameras inside kidneys. Stones form hidden from sight and all we have is the final results.
So, we need hypotheses about how they form.
Hypotheses About How Kidney Stones Form
Hypothesis means a vision of how what our senses show us might have come to pass.
But not only a vision. The vision must offer necessary deductions about the world in which we can measure things. Otherwise the vision is mere speculation, airy conjecture. Only visions that offer such deductions warrant the name ‘hypothesis.
Of those, only some have utility. In other words, the deductions from only some hypotheses lead to measurements we know how to make. As an example, right now we cannot make time lapse movies from inside human kidneys that show kidney stones forming.
Useful or not, all hypotheses begin as dreams – imaginations, inspiration. They come to us when we have a clear knowledge of what is there and have a passionate desire to know what our senses cannot tell us. In this case, how those stones that we find growing came to grow that way.
Where Kidney Stones Grow
With that in mind, and to begin with, what exactly do we know?
One thing we know for certain: clinically significant calcium oxalate kidney stones grow in human kidneys attached to ‘plaque’ – deposits of calcium phosphate embedded within kidney tissue.
Another: Calcium phosphate deposits plug the terminal ends of kidney tubules. On the open ends of such plugs – ends that face onto the urine – small rounded overgrowths form. They contain mixtures of calcium oxalate and calcium phosphate. We believe they detach and grow into significant stones – stones big enough to cause pain, obstruction, need for surgery. But we do not know for sure because we see and harvest overgrowths only a few millimeters around – too small to do much to patients.
Often we find stones attached to nothing. They bear on their surfaces no traces of a prior attachment site. We believe such stone stones form in urine – not necessarily attached to anything.
In the left panel of this picture, the arrow touches a calcium oxalate stone growing on a papillum of one of our patients who gave us permission to photograph during kidney stone surgery.
Like a shoebox filled with family snapshots the article linked to the header has many more images like this one.
The surgeon, with some effort, pulled the stone off of the papillum.Turned upside down that stone reveals a small light patch of calcium phosphate that once linked it plaque. That exact patch of plaque lies at the upper left of the right side of this picture. A big arrow points to it.
The white patch on the stone fitted exactly into the slightly darkened center of the plaque. Irregular as clouds, more plaque lies scattered about on the surface.
Evidence from Stones
Because stones that grew on plaque often take their anchoring site with them when they detach, scientists can use that site to estimate the frequency of such a mechanism. In our study detailed in the main plaque article whose link heads this section most stones found free in the kidneys bore this signature of origin. Sometimes under a microscope tubule fragments are visible.
How often does this occur? We found growth on plaque on many of our patients but we looked for it. By contrast, others who looked merely at all comers found it less often. Though exciting controversy for insiders the final count bores me. After all, urological surgeons must eventually report on case series and get us the answer. Right now I can say stones grow this way, in people.
How Does the Stone Grow Over Plaque?
Urine Contacts the Tissue Plaque
While we wait, I have a lot more to tell you. Most of the plaque you see in the picture is inside the shiny membrane that covers the papillary surface. So long as the membrane covers it stones cannot form. But where the stone grew that membrane gave way. Urine bathed the exposed plaque and minerals from that urine formed the initial hydroxyapatite binding site that shows up at the bottom of the stone in the right hand panel of the picture.
Hydroxyapatite (HA) Grows Over Exposed Tissue Plaque
This very simplified drawing shows that sequence.
Through this part of the kidney the final urine flows out through the collecting ducts that open through tiny holes too small to see in the photograph. The blood
vessels of the papilla run hairpin shaped down then back up – vasa recta. That part of the nephron critical to water conservation – the loops of Henle – runs the same way, hairpin shaped. So their fluid runs down into the papilla and then back up.
Between them I drew in some plaque shaded in a grainy oval. It grows in between the vessels and loops. That space, because it lies between things, we call the interstitial space. Cells fill it. Some of those cells run at right angles between the loops and vessels – like steps of a ladder. Others simply pack in like marbles in a glass vase. Plaque lies between the cells.
I drew the covering curved outer membrane as gapped so plaque extrudes through it. The final urine run comes out of the collecting ducts and films over the papillary surface, thence over the exposed plaque. I drew in the hydroxyapatite (HA) connector and the body of the stone – CaOx. When that stone breaks off free into the renal pelvis – the whole right side of the drawing – it can so what stones do. It will carry with it the plaque that once held it in place.
Plaque Forms in the Loops of Henle
How could be know this? We find the plaque but we cannot watch it form.
This way. Find the smallest possible deposits, deposits so small we need powerful microscopes. Where is it? Plaque begins like all crystals, as tiny nuclei that grow, so the formation site will contain very small deposits.
That is not sufficient. Look for the site that always contains plaque even when the amounts of plaque are tiny. Possibly that could be between the interstitial cells. Or in the walls of the vasa recta, or the loops of Henle. Maybe, in the interstitial cells.
Of these, the loops won the prize. The most minute deposits lie in their walls. The blowup in the picture shows four cells lining a length of a loop segment. Between them the red arrow stands for tubule fluid. On their bottom sides run the basement membranes that face onto the interstitial space.
In those basement membranes we find plaque originates. From them or over them plaque expands between the loops and vessels until it reaches the papillary covering membrane. It lies beneath it, dormant, until some breach of that membrane permits urine to contact it whereupon a stone can form.
What is the Science?
Such fancy talk but this seems all description – our senses show us the whole story. Or, do they?
What We Know
We know clinically meaningful stones can form on plaque – for that we need only our photographs. We also know that when stones grow attached to the surfaces of papilla they attach through plaque not just to any part of that surface – the main article gives the evidence. Stones seem to grow on plaque like a sandwich – plaque, overlay of HA, overlay of CaOx. But only two complete stone – plaque samples have been studied.
What We Think We Know
If you watched carefully I did a slight of hand – slipped in a hypothesis. Where plaque forms we will find the smallest particles. In all plaque deposits that same place must always contain plaque.
Watch the word ‘should’. I inverted a hypothesis. Here is the real vision – hypothesis. Plaque forms somewhere particular – not just anywhere and not just everywhere. If that were true, then we should find a place or places where it begins. Such places should have plaque whenever we find it and should contain the smallest particles because crystals begin as atom size nuclei and grow.
We found such a place so presently we believe plaque forms in basement membranes of loops.
We also believe stones form over plaque in a sequence – HA then CaOx. But we published only two attached stone – tissue complexes. Each study, being fiendishly difficult, took months. We need no hypothesis here, but more studies. Funding agencies, however, so detest repetition they demurred when we tried to get money for it.
What We Do Not Know
Of course, what fraction of CaOx stones grow on plaque.The experience of thoughtful surgeons will inevitably answer the question, so scientists need not bother themselves. Even so it is something to find out.
Another is what makes the outer membrane give way – why should it. Something acts to cause the breach. What?
A third: What makes stones assemble themselves sandwich-like as I described?
Although we believe so, does plaque really begin in the basement membranes of loops of Henle?
Finally, what produces plaque? Though necessary, local supersaturation need not suffice. Even if local supersaturation did suffice, what causes it in kidney stone formers? Normal people make stone plaque, many CaOx stone formers make more than normals. Why?
For most of these questions we need useful hypotheses, available some not.
The main article illustrates plugging and the science we have. But what does plugging mean to stone formers, physicians, scientists? Where are we in the science?
This table, once I explain it properly, tells the main story.
We made intraoperative photographs and biopsied kidneys of patients who formed kidney stones for different kinds of reasons and cataloged whether stones grew on plaque and whether tubule plugging occurred. Here is our yield as of 2015.
Many Diseases Cause Kidney Stones
This site has focused on stones not due to systemic disease. Called ‘idiopathic’ because without overt cause they are the most common kind of stones.
But plugging requires we speak about all the causes. A glance at the table tells you that all forms of stone studied thus far produce plugging. Plaque is a less general phenomenon. I describe stone growth on plaque in detail because clinically important stones surely form that way. But we cannot say such stones clearly form on plugs.
Stones Idiopathic and From Diseases
When we speak of the broad range of common stones we mean idiopathic calcium oxalate stone formers (ICSF), and hydroxyapatite (HA) and brushite (BR) stone formers. Full articles detail the ICSF and the HA and BR stone formers. Plugging is universal in HA and BR stone formers. As expected, HA or BR admixed with CaOx make up the plugs. The overgrowths are HA and BR respectively, mirroring their stones, those on plaque and ‘other’ stones found in the kidneys but not attached to plaque.
The ICSF stand apart. Among our first 30 cases we found no plugging. Among a second group of 7 cases we found one with plugging. The main article on ICSF contrasts what we found with another published report that describes plugging in many ICSF, mostly older women. Our ICSF, by comparison, were mostly younger men. I alluded to this statistical controversy just above: What fraction of calcium stone formers grow their stones on plaque? The table makes clear that all three groups from stones on plaque but ICSF stand out for their emphasis on that mechanism.
Stones From Diseases
Small bowel resection (SBR), ileostomy (ILEO) and primary hyperparathyroidism produce both stones on plaque and marked plugging. In all six conditions that feature stone growth on plaque the stones growing there are CaOx and HA. The plugs puzzle us. Urine is very acid in ileostomy yet plug crystals are HA and sodium acid urate (NaU) which both form in rather alkaline urine. These contrast with their CaOx and uric acid (HA) stones that both form well in such an acid urine. SBR raises urine oxalate so we expect CaOx stones. But why HA plugs? Urine is not alkaline. Small bowel bypass for obesity also raises urine oxalate, and once again plugs are HA. Why? On the other hand, PHPT offers no puzzles. Urine is high in calcium and often alkaline, plugs HA that forms well under such conditions.
Bypass, renal tubular acidosis (RTA), cystinuria (CYS) and primary hyperoxaluria Type 1 (PH1) produce no stones on plaque – in fact produce little plaque altogether. As one might expect, plugs are HA with some CaOx, cystine, and CaOx, respectively – no surprises here!
What Plugging Means
Plugs Form At the Ends of Nephrons
Crystals of the sort in the table plug the terminal ends of nephrons. Those of you not physicians probably know – or can now learn – nephrons are tubes that begin with filtration and end in a final urine. Kidneys each have about one million of them and their combined small drops of final urine make up what we produce each day.
That final urine leaves the nephron, obviously, at its nether end – furthest from its beginning at the filtration point. We name that final short end – a few millimeters long – after its first describer: the duct of Bellini (BD). It looks different from what comes before it, and in it plugs form. Just above, the inner medullary collecting ducts feed into the BD. It is in BD and IMCD we find the majority of plugs. Rarely, crystals plug higher up, in the outer medullary ducts or cortical collecting ducts, or even the loops of Henle. So plugging occurs more or less at the ends of nephrons.
Tiny Overgrowths Form Over the Ends of Plugs
Small overgrowths over the open ends of plugs may detach and grow into stones. The idea has obvious merit and reasonability. But unlike stones on plaque that often achieve clinically relevant size – 2 to 3 millimeter, plug overgrowths are often less than a millimeter. I believe these tiny knobs do become stones. We need a test of this idea and I cannot think of one. For example, might we imagine a mark like detached plaque?
They Injure and Obstruct
But this is to simplify matters too much. The many nephrons join each other as small streams and rivulets join along their ways to make larger channels that themselves merge, gradually forming, perhaps, a mighty river, even. So on the surface of each papilla one finds a few dozen BD and given nine or ten papillae in a kidney a few hundred to drain the fluid of a million nephrons.
This means what it would mean to dam up the outlets of many small streams – fluid would back up, pressures, therefore height, increase. One might expect that high up in the nephron, far from the dams, tubules would dilate or other signs of injury appear. More; unlike such an outlet living cells line BD that crystals might injure. This means we should expect signs of injury, low down and high up, and we do. Injury is easy to document.
Injury From Plugging
The main plugging article makes clear that plugged tubules sustain a lot of injury. The lining cells are absent. Crystal plugs fill the whole interior. They adhere to the basement membrane on which the lining cells once rested and through which they once drew their nutrients from and gave up their waste products to the kidney circulation. Said another way, a tube lined by living cells becomes a mere tube filled with crystals.
The cells around the tubule, those interstitial cells I wrote about in the section on plaque, know what happened. They wall off the destroyed segment in fibrous tissue. The process of such walling off is a form of inflammation. These cells respond to the cell destruction so as to isolate the problem in scar.
All this happens in the papilla, the very end of the line from nephrons and the final urine. Surgeons can see the plugs and the scarring and deformity from inflammation. In the common idiopathic calcium phosphate stone formers plugs are numerous and small. Plugs are sparse in those who make brushite stones, but very large. Renal tubular acidosis causes small deposits but so numerous as to severely damage the papillae.
The main article shows pictures and a video of all this damage. What matters here is that plugs certainly damage papillae and lead to scarring.
As a rule, papillary injury rarely results in loss of glomerular filtration, the life sustaining function of kidneys. Even so, biopsies from the kidney cortex where the glomerulae reside show more injury in patients with plugging than in those with just plaque.
We did not put this picture into the main article about plugging. For the brushite (solid circles) and HA stone formers (open circles) in the table we obtained biopsies not only of papillae but also the kidney cortex. Likewise for the idiopathic calcium oxalate stone formers (triangles) who make only plaque.
The scores along the baseline – 0 to 3 – are grading done by a skilled kidney pathologist who know nothing about the patients. They grade tissue injury in the tubules and interstitium of the cortex. The vertical score grades injury to the glomerulae themselves.
ICSF had low scores for both, mostly 0 and 1, as one finds in normal people. A sample of their kidney is at the bottom right – even if you know nothing it looks good.
The HA and BR stone formers had almost all of the glomerular injury and tubular injury scores above 1. Their tissues, right middle and top, respectively, look more complex and irregular. Scarring and loss of nephrons are apparent to those trained in this work.
Despite scarring and injury, kidney function as we usually measure it does not differ between these three groups of patients. Neither are they lower than normal people. Perhaps kidneys have considerable reserves. Our estimates of kidney functions certainly are crude and may not detect injury until more marked than this.
In more extreme cases, however, such as with RTA, the bowel diseases, and PH1, kidney function goes down and some patients ultimately require dialysis. So when severe enough papillary injury seems very dangerous to health. What saves most stone formers from kidney injury may well be simply that without a systemic disease plugs do not damage papillae above some critical point.
Uric Acid Stone Formers
We have thus far concerned ourselves with calcium based stones but one study on patients whose stones contained uric acid belongs here. One might expect uric acid to plug tubules or perhaps crystallize in the bulk urine. In fact, plaque was about as impressive among the uric acid stone formers as the calcium stone formers, and plugging, too. Plugs could not be analysed, and might have been uric acid or calcium salts. The authors did not say where they found stones growing.
What is the Science?
What We Know
Like for plaque, observation seems sufficient. Facts seem facts. Plugging occurs, overgrowths form on them. Plugs injure – nay destroy – lining cells of tubules they form in. Tissues around plugged tubules show obvious inflammation and scarring. Structures higher up in the nephron show signs of injury and scarring.
Plug crystals and stone crystals overlap in their structures, but may diverge in a given patient.
What We Think We Know
Because IMCD and BD contain the nearly final urine, supersaturation could cause plugs as it seems to cause the HA and CaOx overgrowths on plaque. But ileostomy with its acid urine and HA plugs belies this idea. That crystal would dissolve in the urine yet formed and remains in the tubules.
We imagine plug crystals injure tubule cells via mechanisms cultured cells exhibit when exposed to crystals, or cells of rodents that form plugs because of massive oxalate loads. But human cells may not do the same, and only one human disease produces such consistent CaOx plugs as occur in oxalate loaded rodents – PH1. Most of all we surmise that plugs somehow anchor proto stones so they can grow into clinically important sizes.
What We Do Not Know
What causes plugging apart from supersaturation. Likewise, how do plugs in human kidneys kill cells and produce inflammation in surrounding tissues. Do plugs really lead to clinical kidney stones?
More interesting – what happens to plugs? Do the damaged BD slough and the tubule repair itself from above, or below? Do plugs perhaps form in normal life and disappear as part of a general kidney repair process?
What about uric acid stones: do they form on plaque? Does uric acid plug tubules? We need simple observations.
No link arises from the bold heading as no article considers stone formation from simple crystallization in tubule fluid or urine. Plaque, plugs, stone growth on plaque, and even overgrowths on plugs all arise on cell or fixed crystal surfaces.
But several conditions may illustrate free solution stone formation – medullary sponge kidneys and cystinuria.
Whereas these patients indeed pass kidney stones of usual dimensions, their sponges often fill with vast numbers of tiny round stones that do not adhere to the lining cells nor appear to evoke any inflammatory response. Their internal laminated structure of calcium oxalate crystals with organic matrix much resembles stones that form on plaque but without the telltale apatite anchor site. Their roundness, tiny size, large numbers and failure to adhere to chamber walls speak to simple crystallization in supersaturated tubule fluid dwelling overlong in stagnant blind end cysts.
Although we offer free solution crystallization as the cause of these many tiny stones, urine supersaturations themselves are meager compared to most stone forming patients. We presume any supersaturation could create these microliths given enough dwell time in cysts.
Plaque is very sparse, and BD and IMCD plugs as well. More or less they are rarely found. Routine kidney stones are usually CaOx and have the usual size range. But because of the cysts filled with tiny stones CT scans show what appears as many stones or tissue calcifications – so called nephrocalcinosis.
MSK presents us with two separate issues – the stone and the disease itself.
Because this chapter concerns how kidney stones form I choose to delay the question of MSK biology into a later time. But the stones fit well.
What is the Science?
What We Know
Clinical stones are usually CaOx and of typical size but cyst chambers contain innumerable tiny, round, micro-stones. They do not damage cells nor adhere to them. Plaque and plugs are rare indeed.
What We Think We Know
Stasis causes the the microliths.
What We Do Not Know
Is stasis sufficient as a cause of microliths? Do the small stones grow into the large ones patients pass? Why do microliths not adhere to wall linings?
This amino acid crystallizes easily. We find cystine plugs but they do not adhere to tubule walls and cannot anchor stones. Plaque is scant. Tubule plugs of calcium phosphate are surprisingly common. Dilated IMCD and BD also are common as is inflammation and injury around plugged ducts and high up in the cortex. In fact, cystinuria seems to damage kidneys enough that clinical measures of kidney function show reductions.
But even here, free solution seems hard to prove because the BD plugs dislodge so easily. How can be know if one or another simply lodges among papillae and grows? Likewise for tubules. We can say cystine crystallized in tubule fluid but what about the calcium phosphate plugs. How do we know if they somehow condition tubule cells to promote cystine crystallization.
What is the Science?
What We Know
Cystine plugs BD but HA plugs BD, too, and IMCD, and even thin limbs of the loop.
What We Think We Know
SImple supersaturation of tubule fluid causes cystine plugs.
What We Do Not Know
Why do so many BD and IMCD dilate. What causes so much inflammation in the papillae? Why of all the conditions does kidney function so clearly fall below normal? Is it just that stones can grow large, that many surgeries occur?
Summary of Chapter Two
With perhaps one or two exceptions, stones seem to grow on some kind of anchoring surface – plaques or plugs. Exactly how plaque and plugs form, and what we might do to reduce their formation are both open research questions. SImple crystallization in free solution may produce plugs but given the biology of tubule lining cells that hypothesis would be difficult to test. Reduction of supersaturation remains our main treatment for the stones themselves. Because plugging causes cell death and tissue inflammation treatments to prevent plugging may have clinical value apart from stones themselves. The hypothesis that reduced supersaturation might reduce plugging could be tested, in principle.