This word is commonly used to describe stone disease.
It can sound worrisome for patients.
Physicians tend to think about uncommon diseases which cause stones.
Scientists think about crystals in kidneys of humans and animals, and theorize about their causes.
But the term has become vague and blurred, we believe, and in need of sharpening. That is why we wrote this article.
Because the material is complex, we have added summaries in bold italic at the top of sections that might pose problems for the non technical reader.
Lacking such a summary, read on confidently.
WHAT DOES ‘NEPHROCALCINOSIS’ MEAN?
The boyish face is Fuller Albright, perhaps the greatest 20th century scientist concerned with kidney stones. The lovely biography Alexander Leaf wrote in his honor for the National Academy of Sciences tells of his brilliant career and unfortunate later life illness.
Fuller Albright Made Up the Word
All scientists find their special part of the real world to study. His was the bodies and biologies of patients with kidney stones, especially those with hyperparathyroidism – a mineral disorder caused by enlargement of one or more parathyroid glands which we have not as yet discussed on this site.
In 1934, young Albright, then an Assistant Physician at the MGH and an instructor in medicine at Harvard Medical School penned a remarkable paper (this is a link to a PDF) in which he presented to the world, almost as an aside, his newly coined ‘nephrocalcinosis’ to describe calcium deposits in kidneys of patients with hyperparathyroidism. (This is the web link to the paper; Kluwer publishers makes you pay for a copy).
Who Were His Patients?
Albright described three types of kidney involvement in primary hyperparathyroidism.
Type 1 is simply formation of kidney stones.
Type 3 is an acute ‘parathyroid poisoning’ with kidney failure and, at that time, death.
Type 2 was midway between these as there were calcium deposits in the kidney tissues but kidney function, though usually reduced, was adequate.
In Type 2 cases he wrote this about the word.
The tissues he observed and those in his references came from autopsies.
Kidneys were scarred and contracted, with calcium deposits in the cortex and medulla.
His own index case – whose tissues he did not obtain – had kidney disease.
Simple stone formers without kidney disease are our interest on this site and in this article. They do not come to autopsy very often, and he did not have tissues from them. They were his Type 1 cases.
So when albright coined the word nephrocalcinosis, he was surely referring to patients with primary hyperparathyroidism who went on to chronic kidney disease and renal failure. Their kidney calcifications were a mixture of those in common stone formation and those that occur with phosphate retention and kidney failure.
Who Are Our Patients?
We are concerned with patients whose kidneys would have been like this Type 1 cases: No obvious kidney disease, kidney stones, and – he did not and could not have known this – modest amounts of calcium deposits in their kidney tissues.
Most of our stone formers have no obvious systemic disease, like hyperparathyroidism. They are called ‘idiopathic’ stone formers, meaning caused in themselves.
Apart from recent work by us and two other research groups their kidney tissues have not been studied in detail, so the pattern of crystal deposits is newly described. Albright could not have studied their kidney tissues, and would have thought all of their calcium deposits were simply urinary tract stones.
But not all of our patients are idiopathic stone formers. Some have hyperparathyroidism, some bowel disease, some uncommon diseases like cystinuria and renal tubular acidosis and primary hyperoxaluria. But almost none would have come to autopsy, so Albright would have known little about their kidneys.
It is modern technology which has allowed us to make observations of the kidney tissue in these diverse states.
We have written this article, to summarize the deposits in common idiopathic calcium stone formers, and in stone formers with a variety of disease, and thereby make good on Albright’s neologism: Say what it is that is in the kidneys of stone formers, including his favorites – those with hyperparathyroidism.
Who Uses the Word Right Now?
Radiologists, for the most part. And what they mean is that ‘calcified’ – radio dense – material overlays the outlines of the kidneys on various kinds of imaging studies: Simple flat plates, ultrasound studies, and CT scans.
But radiographs are to the reality of tissue as in the Cave of Shadows allegory: Images projected on the wall of a cave, semblances of real objects held before the fire. And those in the cave, who can see only the shadows, theorize about what is really there and how it came to be.
Patients can be confused and alarmed by the term ‘nephrocalcinosis’. We believe clinicians and even scientists sometimes exhibit some confusions, too.
Our purposes here are to pin down what the word should mean today, and ask if it is even valuable to retain it as a diagnostic term.
What Does the Word Lead Us To?
The problem with this word today is evident if you look it up in PubMed. Try that – limit your search to humans and ask for reviews. Here it is: (“nephrocalcinosis”[MeSH Terms] OR “nephrocalcinosis”[All Fields]) AND (Review[ptyp] AND “humans”[MeSH Terms]).
There are 273 entries. The first 40 are about diseases which can entrain calcifications in kidneys. On the list are medullary sponge kidney, kidney transplant, distal renal tubular acidosis, primary hyperparathyroidism, inherited disorders of the kidney, hyperoxaluria, loop diuretics in neonates, vitamin D and A toxicity, FAM20A mutations – enamel renal syndrome – claudins, hypomagnesemic states, and hypophosphatasia.
Just to be sure, I went on to the next 20 and found much the same.
If you clear the requirement for reviews, the list lengthens. There are 1895 results. But the range of diseases is about the same.
Nowhere did we find simple, idiopathic calcium stone disease.
If you clear even humans, there are 2686 entries, and the range of diseases remains more or less the same. However, within the first 40 entries you come upon our recent work, in humans, a single center review from Italy, and the review from which this this article takes its starting point: ‘What is Nephrocalcinosis?’ by professors Shavit, Jaeger, and Unwin.
That excellent review begins, as one might expect, with a proper definition: ‘Strictly, the term ‘nephrocalcinosis’ refers to the generalized deposition of calcium oxalate (CaOx) or calcium phosphate (CaPi) in the kidney.’
What Do We Propose to Offer Here?
Where are the renal deposits of calcium that have been demonstrated to date?
What are the deposits made of?
In what diseases are deposits of a specific kind and location found?
What do they look like during stone surgery or at renal biopsy – the modern way people will see the kidney?
What should scientists, physicians, and patients think about when confronted with or when using the word ‘Nephrocalcinosis’. Should we continue to use the word?
WHERE IS NEPHROCALCINOSIS?
This section names and describes the parts of the kidney and of the individual nephrons which make it up. Each normal adult kidney has about one million nephrons. It is helpful to read this section as a background and use it as a lookup for later sections.
Where Things Are
Cortex, Medulla, and Papillum
The upper 1/3 of the kidney slice, above the crescent of red and blue vessels is the cortex. In it are the filtering units that begin the nephron, the glomerulae, shown as round balls.
Below the crescent is the medulla. As the medulla narrows, its blunt end is the papilla.
Each glomerulus drains its filtrate into a squiggly – convoluted – ‘proximal’ tubule which gives way into the remaining nephron.
The portion labelled ‘Thick Descending Limb’ is actually a straight continuation of the proximal tubule. It gives way to a descending and ascending thin limb, and then an ascending thick limb which drains into a ‘Distal’ convoluted tubule’, and thence through an unmarked straight connecting segment into the collecting ducts which run from the cortex down into the medulla and thence into the papilla which contains the bottom of the long hairpin loop and the termination of the collecting duct into the urinary system.
The medulla is divided into two regions: Outer medulla, from the crescent to the bottom of the thick ascending limbs; Inner Medulla, from the bottom of the outer medulla to the papillum. There is no special anatomical divider of the papillum from the inner medulla; the papillum is basically the last few millimeters of the medulla.
The outer medullary and inner medullary collecting ducts (IMCD) differ somewhat in their cell types and appearances. Ducts of Bellini (BD) are the terminations of the IMCD and empty the final urine into the urinary collecting system through tiny holes in the lining of the papillary tip.
Crystal Deposits in the Cortex
The cortex usually has no deposits in most stone formers. This section is here because physicians and scientists who read this would expect completeness. Feel free to skip it.
The only relationships to stone diseases concern hyperoxaluric states, ileostomy, primary hyperparathyroidism, and APRT deficiency. Often, cortical calcifications reflect kidney diseases.
These rarely calcify. Intravenous dibasic phosphate in rats, rare consequence of marked hypercalcemia, calcifications of large immune deposits can occur. Vitamin D intoxication in suckling rats can cause it. Overall, it is a curiosity.
We have provided information about proximal tubule S3 segment calcification in hyperoxaluric states with greatly reduced renal function. 2,8 dihydroxyadanine crystals due to APRT deficiency can plug proximal tubules. In transplanted kidneys we have seen scattered birefringent crystals presumably calcium oxalate.
Distal Convoluted Tubules and Cortical Collecting ducts.
Acute phosphate nephropathy from bowel preparation is well known. Distal convoluted tubules contain calcium phosphate deposits in cystine and primary hyperparathyroid patients and calcium oxalate in primary hyperoxaluria stone formers. In transplanted kidneys tubule and interstitial deposits are found not rarely and are said to be calcium phosphate. In primary hyperparathyroidism with stones, and ileostomy patients, deposits were found in the cortical collecting ducts.
As well as in transplant kidneys, chronic kidney disease has a very high frequency of kidney cortex calcification. WIthin that rubric interstitial calcifications are common. Primary hyperoxaluria patients with reduced renal function may have cortical interstitial deposits composed of calcium oxalate at the sites of proximal tubular deposits.
What about Cortical Blood Vessels?
To us these are in and critical to but not kidney tissue. We believe it is potentially confusing to lump vascular disease and its associated calcifications in with calcifications within the renal tubules and interstitium.
Crystal Deposits in the Medulla and Papilla – Work by Us
This is useful for everyone. The names of kidney structures are all defined in the prior section with the picture. All kinds of stone formers can have crystal deposits like this and may want to understand more about them. This is modern nephrocalcinosis.
The tissue calcifications related to kidney stones are mostly in the medulla and papilla. Biopsies have been reported by our group, and also several others. We combine here all reports to date.
As a general rule, some tissue calcium deposits are present in virtually all stone forming people. We mean by this that excluding clinical stones – the things that enter the urinary collecting system, pass, and cause pain, obstruction, bleeding, and other miseries – the tissues themselves almost always contain deposits.
These deposits are of three types: Plugs of crystals in various segments of the nephrons; calcium phosphate deposits in the interstitium; tiny micro – stones in the dilated tubules of patients with medullary sponge kidney disease.
These three types of deposits are themselves distributed variably among the eleven definable calcium stone forming phenotypes studied to date: Idiopathic calcium oxalate stone formers (ICSF); Idiopathic brushite stone formers (BR); idiopathic hydroxyapatite stone formers (HASF); distal renal tubular acidosis (dRTA); primary hyperparathyroidism (PHPT); primary hyperoxaluria type 1 (PH1); small bowel resection (SBR); ileostomy (ILEO); obesity bypass (BP); cystinuria CYS); medullary sponge kidney (MSK).
Thick ascending limbs
No deposits have been found in any stone formers to date.
Thin Loops of Henle
We have found rare hydroxyapatite deposits in ileostomy, cystinuria and primary hyperoxaluria patients with reduced renal function. These are best illustrated in Figure 4 of the ileostomy reference. No other research groups to date have reported deposits.
Outer Medullary Collecting Ducts
Patients with primary hyperparathyroidism are the only stone formers who show deposits (calcium phosphate) in this tubular segment.
Inner Medullary Collecting Ducts
Crystal intraluminal plugs have been found in all eleven stone forming phenotypes examined. The majority of these plugs are composed of hydroxyapatite.
Bypass, distal renal tubular acidosis, small bowel resection, and medullary sponge kidney stone patients possess calcium oxalate deposits.
Mixture of sodium acid urate and ammonium acid urate was admixed with biological apatite in ileostomy stone formers.
Note the above link goes to an article on this site which lists 10 phenotypes; ICSF, the 11th phenotype, did not reveal collecting duct deposits in our work but deposits of HA were found in cases of ICSF reported by Wang et al.
Microliths, myriads of extremely small, round, non-adherent stones have been found only in the dilated IMCD of MSK patients. These differ from plugs in virtually all respects. Plugs adhere to IMCD lining cells and cause cell damage, and death, MSK microliths do not adhere nor cause any perceptible damage. Microliths are round, not cylindrical, and made up of concentric layers of crystal; plugs also have layers but much less regular.
Cystine plugs also differ from all other plugs in not adhering to tubule cells. They move freely and do not appear to damage the cells.
Ducts of Bellini
Crystal intraluminal plugs have been found in all stone forming phenotypes examined and in similar patterns to that described for inner medullary collecting ducts. Brushite stone formers possess intraluminal plugs of a mixture of brushite, apatite and calcium oxalate plugs while plugs in cystine patients possess only cystine. The intraluminal plugs found the ducts of Bellini are unique in that they may have an overgrowth at their distal end as it protrudes through a dilated opening of the duct.
To date, all interstitial deposits found in human kidneys have been hydroxyapatite. The primary pattern of interstitial (Randall’s) deposits seen as single multilayered spheres when located in the basement membrane of thin loops of Henle and embedded within a matrix when located in the interstitial space. Two different patterns of these deposits have been reported in apatite stone formers: the typical Randall’s plaque and NIPS (new interstitial plaque structures); both are hydroxyapatite.
What About Blood Vessels?
No evidence exists showing calcium deposits within the vasa recta within the medulla or papilla. Deposits of hydroxyapatite can be found within and involving capillaries, but this is not evidence of a primary calcification. Theoretical papers proposing vascular injury and calcification as causes of plaque have failed to advance direct evidence in support of the theory.
Crystal Deposits in the Medulla and Papilla – Work by Others
For the non technical, this can be skipped; it is our proper obeisance to the excellent work others have done.
Wang et al compared ICSF with large and small amounts of interstitial plaque. In all the cases they found plaque as we do, deposits were at the thin limbs and interstitium. Those with hypercalciuria had the heavier plaque deposits, much as we have found. They also show IMCD intraluminal deposits, which we have not shown to date. They did not analyse the crystals in the plugs
Linnes et al studied ICSF, ICSF with malabsorption, phosphate stone formers which included struvite stones, and uric acid stone formers. In 99% they found interstitial plaque with an average low abundance. It was only when they separated out hypercalciuric ICSF that they found high plaque abundances as we have. They found plugging in all stone phenotypes, in medullary collecting ducts and also by endoscopy – this latter means they say BD plugs at surgery. The patients were mostly female, and hypercalciuria was not impressive. As in the former paper, they did not analyse the crystals in the plugs.
Khan et al described a single case in which they found interstitial plaque deposits which were identical to what we have described. The clinical phenotype was not described; the patient had large calcium oxalate staghorn stones. By EDX analysis the interstitial deposits were calcium phosphate. Tubule plugs were found in the medullary collecting ducts and these were calcium oxalate. We suspect this patient had primary hyperoxaluria.
Khan et al examined biopsy tissue from 15 patients with ‘idiopathic calcium stones’ not otherwise characterized in the report. Large areas of interstitial plaque were found. Crystals were HA. No plugging was found. Stones were calcium oxalate. The main finding was intimate association of plaque with collagen, as we have also described.
Overall, these four papers more or less agree in substance that interstitial deposits are common and composed of calcium phosphate. Likewise plugging is common and plugs are variable. Only we and Khan have described the crystals in plugs to date. Because the images of the tissues from these four papers do not differ from ours, we have not added their pictures here.
It is not so important to us that these papers agree with our findings, but that they agree with one another and with our findings. This is helpful as it shows more or less that crystallizations in kidney tissue of stone formers are found to be about the same from multiple laboratories, and therefore we can begin to form a consensus about them.
WHAT IS NEPHROCALCINOSIS
Can We Summarize What Was Just Said About Crystals in the Kidneys?
The foregoing makes only a few main points.
In stone formers of all kinds there are only three kinds of crystal deposit.
One is plaque – calcium phosphate as hydroxyapatite – in the interstitium.
Another is plugging of the lumens of the various tubule segments, mainly the medullary and papillary collecting ducts. These plugs are usually calcium phosphate but can be calcium oxalate, cystine, or uric acid salts.
A third is the microliths of MSK, unique to this one disease.
Why Are Plugs and Microliths Not in the Cortex?
The kidneys extract water from the tubule lumens progressively, concentrating the salts – like calcium phosphate and calcium oxalate – which eventually end up in the urine. Plugs increase progressively as water is extracted.
That is why all 11 diseases have some plugging in the papillary collecting ducts.
Where is the Interstitium?
Envision a tall building. Pipes run from the basement to the roof – water, steam, drains.
Electrical conduits, the same.
Elevator shafts, and stairwells the same.
Now, think about the space between the elevator shafts, stairwells, and all the pipes and conduits: That is the interstitium.
The word means standing between.
In the kidney the long structures are the tubules and vessels; the interstitium is the space between them. That is where plaque is. There are cells in the interstitium – it is as though, as an example, insulation blocks were stuffed into the spaces between pipes in my building.
Put more bluntly, mice can live in the spaces between things in a building, but not in the pipes. Rust can plug pipes but not the spaces between them. (We know the analogy is not perfect; permit us a little room here).
Let’s return to where we started.
Albright never would have seen much of what we have shown here. He had no access to biopsies of kidney papillae, nor surgical visualizations such as have now become commonplace.
He could not have known the crystal composition of the tiny deposits.
But the deposits in the kidneys are what he meant by nephrocalcinosis: Calcium deposits in the kidney tissue: Plaque and plugs.
The excellent review by Shavit, Jaeger, and Unwin concurs with Albright: ‘Strictly, the term ‘nephrocalcinosis’ refers to the generalized deposition of calcium oxalate (CaOx) or calcium phosphate (CaPi) in the kidney.’
Given what they have said and all that we have reviewed here, nephrocalcinosis itself is, in any one patient, interstitial calcium phosphate crystals, tubule crystal plugs of diverse kinds, or both, and microliths in the dilated tubules of MSK.
That is all that has been seen in human kidneys and therefore it is the reality of nephrocalcinosis.
It is what the word meant at the beginning.
It is what the word means now.
We propose the word be restricted to this exact meaning: Calcifications within kidney tissues as demonstrated directly in the tissues themselves.
WHAT ELSE CAN PEOPLE MEAN BY ‘NEPHROCALCINOSIS?
The reality of tissue plaque and plugs is inferred from how the kidneys appear on CT scans or other radiographs and during surgery. Actual biopsy such as we have reported is a research procedure.
As in Plato’s Cave of Shadows, the true tissue calcifications, the reality of things, can appear variably in the confining shadows of the radiologist.
We propose the term ‘radiographic nephrocalcinosis’ be used to define this condition, for such a term is exact within its purview.
What matters especially is that radiological means cannot reliably distinguish masses of tissue plugs or of microliths in MSK from stones.
The post by Michael Borofsky on MSK contains excellent operative images of plugging and plaque. Likewise, one of us (AE) had provided two fully illustrated posts, on plaque and plugging. In these are multiple intraoperative views of papillae with a variety of plaque and plugging patterns.
Abundant plaque is frequently observed during routine percutaneous nephrolithotomy and ureteroscopy in idiopathic calcium oxalate stone formers, idiopathic apatite and brushite stone formers, and in patients with small bowel resection, ileostomy, and primary hyperparathyroidism. It appears as whitish, irregular areas beneath the urothelium usually near the tip of the papilla.
Stones frequently grow attached to plaque.
The papilla in distal renal tubular acidosis, cystinuria, primary hyperoxaluria and medullary sponge kidneys reveal darkish spots or shadows on the surface that represent large intratubular deposits.
Such deposits also can appear as yellow plaque – cylindrical elongate yellow tinged objects beneath the urothelium which are plugs within IMCD and BD.
Using a laser, surgeons can remove the urothelial roof covering these deposits and release the deposit. There are reasons to think this may relieve pain in patients with pain in the absence of obstructing stones.
In some patients, mineral overgrowths protrude from the dilated openings of ducts of Bellini.
These overgrowths are attached to the distal ends of plugs located in ducts of Bellini. One can extract the overgrowth/plug complex intact for mineral analysis, but this is not presently an accepted clinical practice.
t has been suggested that the overgrowth may detach from the distal end of the plug and consequently form a stone lying freeing in the calyx. However, there is no evidence as yet to support this idea.
Ductal stones in medullary sponge kidneys are free floating in the lumens of greatly dilated inner medullary collecting ducts. The appearance of MSK is diagnostic as seen during surgery.
WHAT CAN RADIOLOGISTS TELL SURGEONS?
On CT there is mineral in the papilla: Is it stones which can be removed, or tissue mineral that usually need not be removed? No one can tell right now until the surgery.
The primary pattern of papillary calcification that radiology can detect is intraluminal mineral deposition (tubule plugging and microliths) in diseases that produce enough of it to show up on a CT scan: Primary hyperparathyroidism, distal renal tubular acidosis, medullary sponge kidneys, and some advanced cases of idiopathic calcium phosphate stones.
CT scans cannot resolve individual tubular plugs but reveals many adjacent plugs as a field of parenchymal calcification.
Radiology cannot accurately detect plaque.
Radiology cannot reliably distinguish large plugging or microlith deposits from small stones.
Because radiology cannot accurately distinguish plugs from small stones, surgeons must examine each part of the kidney to be sure all stones are removed.
The benefits of removing tissue mineral deposits is presently unknown.
WHAT DOES ALL THIS MEAN RIGHT NOW?
Here it is, the venerable bottom line:
Radiological ‘nephrocalcinosis’ can be stones, plugging / microliths of MSK, or some combinations of these three.
Removal of stones is an accepted and important surgical undertaking in patients with pain, bleeding, obstruction, or even recurrent infections or special risk of stone passage – eg. travel, pilots.
Removal of tissue mineral is controversial, and few surgeons will do surgery if that is all that is there.
For these reasons, high resolution ureteroscopy is the best alternative when ‘nephrocalcinosis’ is found on CT scan. Once the tissues can be seen directly, albeit from the outside not by biopsy, all stones can be found and removed.
What to do with plugs and microliths is for future trials to determine.