Watch the Video
The video is a big enhancement of this article, I recommend it.
The Structure of Kidneys
Stones form inside the kidneys and the urine collecting system. How they form matters to patients because surgeons can see formation sites during stone removal by ureteroscopy or percutaneous nephrolithotomy. The amount of such sites gives a clue as to future stone risk and also to possible damage done from crystal deposits in kidney tissue.
We cannot discuss where stones form unless you know how kidneys are constructed.
If you already know this, move on. But if you do not let’s stop here and review how kidneys are put together.
The linked article is long, so focus only on the cutaway drawing of a kidney that shows the papillae, renal pelvis and ureter. Stones grow on the papillae.
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.
Growth on Plaque
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
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 dramatic human example of a stone growing on plaque was found years ago, and is probably the best one available.
The stone grew on a stalk that is the calcium phosphate overgrowth on plaque. This is just like the stone with plaque on its underside and its matching plaque I showed in the surgical video image.
This sample has the advantage of showing the plaque in the kidney tissue. It is the black material – calcium phosphate is stained here to bring it out.
The tissue below it is renal papilla. You can see a few end on tubules looking like round tubes.
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.
How Plugs Appear
The picture at the left is a papilla imaged during stone surgery. The end of a terminal collecting duct, from which the final urine issues, is plugged by a mass of crystals labeled by the asterix. The small arrow points to a bit of plaque. The arrowheads show an eroded part of the papilla, that has been injured.
The picture at the right is another papilla photographed from the side of several plugs. You can see they are elongate, like tubes, and that is perfectly realistic. For each plug forms a crystal cast of a terminal collecting duct.
I do not show it but inside any of these plugs the lining cells are dead. The crystal plugs kill them. Around the plugged ducts is a mix of inflammatory cells, drawn to the site by cell injury.
Idiopathic Calcium Stone Formers (ICSF)
The very common calcium oxalate stone formers who have no systemic disease causing their stones tend to form their stones on plaque. As a group they do not exhibit very much tubule plugging. By contrast, those whose stones contain mostly calcium phosphate exhibit plugging and growth on plaque.
Stones From Diseases
More or less all stones arising from systemic diseases cause plugging, with or without plaque. The details will come as we consider each of these separately. This means the idiopathic calcium oxalate patients are the standouts – the ones without much or any plugging. All the rest of the stone formers plug tubule to one degree or another.
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.
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.
Medullary Sponge Kidneys
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.
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.
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.
34 Responses to “Chapter Two: How Kidney Stones Form”
Thank you for this article. I am a 50 yr old female who was diagnosed with MSK after several years of reoccurring calcium stones varying from 2.5 mm to 8 mm. I am currently suffering from an 8 mm stone identified by the ER via CT and will be following up with my urologist shortly. I have been told MSK is a congenital disease and recently was advised to consult an ENT specialist for a possible parathyroid tumor that may be contributing to increased blood calcium levels. Visual inspection of the in office sonogram by the ENT points to a likely benign tumor but I will undergo additional testing to confirm. I’m interested in your thoughts about the connection between the parathyroid and calcium stone formation and whether addressing the tumor (if there is indeed one) will “cure” my frequent calcium stones. I am extremely healthy otherwise. I don’t smoke, don’t consume alcohol, am allergic to sugar cane and corn and any derivatives so my diet is better than most, and I am of a healthy weight. I appreciate your time and eagerly await your response.
Fredric Coe, MD
Hi Tamy, primary hyperparathyroidism is a prime cause of stones and almost invariably curable by surgical removal of the offending gland(s). The surgery is very specialized and should be performed by an endocrine surgeon. Almost always the disease is benign and curable. The article details diagnosis and possible pitfalls. Regards, Fred Coe
Hello. I found this page, and was very interested. Perhaps it can explain my problem. I am 64 years old and had my first stone when I was 23. i have had one stone analyzed, it was a calcium stone. In my left kidney I have a stone 9 mm, it has been there for ages and caused my no trouble. But for the last two weeks I have had a lot of stone attacs. They Are very painfull, some of them so painfull that I wommit. But they last for some hours, and then it is over. I can follow the pain from my back down the urinetrackt. But I cannot see any stones, only tiny small grains. Tiny tyny. But it wont stop, they just come and come. Have had at least Ten now I think. What can this be? Will this go on snd on? What can I do to stop it? Can it come from the big stone indide the kidney. i have been to hospital to remove stones, but I do not get any good follow up. i am really quit desperate now…I take calcium Chanel blockers for my blood pressure. Can they cause it? I eat a low sodium and low oxalate diet. Best whishes from Rikke in Norway
Fredric L Coe, MD
Hi Rikke, You are describing passage of crystals – too small to be stones, easily caught on filter paper – like a coffee filter – and analyzed by infrared spectrum. If I had to guess at are 64 it would be uric acid – sometimes visible as orange or red particles. Your physician can look at the urine under a microscope for crystals – they can be told apart from their morphology if you cannot collect some on a filter. So the first issue is to know what is passing, then prevention is rather simple. Regards from Fred in Lakeside Michigan.
Hi Dr. Coe,
I’m trying to determine if my first kidney stone is a result of genetics (my father has kidney stones) or a side effect of a medication (topiramate). The kidney pain began and above 19 days after I began the medication. Is it possible for a stone to form that quickly? My doctor doesn’t think so but didn’t sound confident and I wanted a second opinion.
Fredric L Coe, MD
Hi Abigail, Topiramate is really a stone forming drug – calcium phosphate stones. 19 days is short, but the drug is a suspect. Stop it, of course, and get another more safe agent from your personal physicians, one that does not inhibit carbonic anhydrase. Then, get a proper evaluation for causes of stones – here is a good introduction to how. Regards, Fred Coe
My stone is 8mm and the first urologist had nicked the ureter trying to get to it. I was told it is embedded in the kidney wall. A new surgeon with a better skill set is now set to attempt to take it out. Mind you I’ve never had symptoms, and they only found it from a contrast because of another unrelated hospital stay. My question is does it need to come out? What implications are there if it stays? They make it sound as if they are only going to get they can and then monitor me every 6 months. By the way the first surgeon did leave the stent in , so I’m wondering if I can just have that taken out? Thanks in advance
Fredric L Coe, MD
Hi Jim, Complicated. If the stone is embedded in the kidney tissue, most folks would leave it alone unless it causes obstruction, infection, pain, or serious bleeding. As for the ureter, the stent is probably left in place to foster healing. As for a second attempt to remove it, perhaps there are surgical indications I do not know about, perhaps the ureter needs to heal up or will need special care. If your new surgeon has the needed skills, it is up to him/her to use them and fix things. I guess I do not have enough facts to add anything more. Fred
Good Morning Dr. Coe,
This was a very interesting read.. thank you. I currently have a 6 mm kidney stone and two smaller ones that are being blocked from passing. I am awaiting surgery to “blast them” and currently have a stent in for 3 weeks which has been very painful. I have so many reasons that could be why I have the stones, (dehydration, 2 years of on again off again antibiotics due to infections from breast cancer surgery, overweight, keto diet, major tea drinker) but I keep looking for how long it can take to create the kidney stones in your body. I have looked on the internet to no avail. Just trying to figure that part out and it will help me to potentially understand why I created this monster.
Thank you for any insight on this and for all you are doing to help us understand this extremely painful medical problem.
Can you please share how long it takes to create…months.. years…
Fredric L Coe, MD
Hi Traci, It depends on calcium oxalate vs calcium phosphate. The latter grow faster – months to years, the former many months to years. But in a general sense, it is possible you produced the nuclei for stones during dehydration and diet changes which grew into the stones. Whatever the timing, I would advise you get fully evaluated now, and treat whatever is wrong. Regards, Fred Coe
Thank you for your response to my question! At this time I don’t know what type of Kidney stones I have, other than the size.
Is it possible to grow a 6mm kidney stone in a couple of months? The reason I ask, I had deep flap surgery in November and was very dehydrated due to the difficulty in moving around. (not wanting to drink and have to use the restroom because it was too painful) Not only did I have the surgery, but developed a very large wound requiring a wound vac most likely till April.
The kidney stone episode happened two months after November surgery, with significant pain, hospital stay, stent surgery and awaiting the shockwave lithotripsy surgery later this week. I will have the stent for a total of 2 1/2 months due to Dr scheduling.
If a 6mm kidney stone can develop that quickly, (2 months) then I will make some assumptions about why this happened to me. Thank you again for your kindness in answering my question.
Fredric L Coe, MD
Hi Traci, Given the history I would be concerned the stones are calcium phosphate or uric acid, which grow very rapidly. Analysis of removed stone material is crucial for treatment, as is 24 hour urine testing. Regards, Fred Coe