I rarely write about new science in stone disease because this site aims mainly at patients and clinicians who want stone prevention now, not in some glittering and distant future. But this article is in the newspapers and promises – as if imminent – something far off and presently theoretical.
It is lovely science, the pictures perfectly gorgeous, the promise wonderful to contemplate in a new and more elaborated world.
But right now, it is just that – promise – so I have taken up my commonplace pen to make things clearer for those of us on the ground, struggling presently with what we have to do what we can do.
The large photograph of the Cloaca Maxima is from the Kandos High School’s website on the ancient city of Rome. I am just taken by it being the work of students fulfilling their course requirements to study ancient Rome and make a website of what they learned. But the actual source is this history blog. I chose it because the authors of the present study studied travertine from an ancient Roman Aqueduct and I thought the Cloaca Maxima, being remarkably ancient, and Roman, might have wonderful rocks, too.
What They Promise
The title: ‘Geobiology reveals how human kidney stones dissolve in vivo.’
Implied in this title, what every patient hopes for – dissolve stones. In their abstract, they say, ‘These observations open a fundamentally new paradigm for clinical approaches that include in vivo stone dissolution…’. They counterpoise this promise against prior assumptions that calcium oxalate stones – the common ones – are ‘…effectively insoluble within the kidney.’
So the work assumes clinical meaning, and offers new hope.
Patients no doubt see this in newspapers. I have. Reporters, properly, emphasize new hope to their readers. Physicians will hear from patients, and want to know what is best to say.
Emily Baumgaertner reviewed the article in the NYT this past September, pointing out: “Doctors often base patient care plans upon the chemistry and molecular components of a patient’s urine. But further research could allow doctors to take advantage of the changing composition of kidney stones themselves, boosting specific ingredients to dissolve the stones completely, without excruciating passage or invasive procedures.”
So, I read the paper, with some interest. As you might expect, given the dramatic opening, how else but to devote a whole article to it, here, as a way of celebrating the new paradigm but making clear – perfectly clear – what and when patients and physicians can hope for actual clinical application of the science.
What I Can Say
Be clear, I am no geologist and about the technical details of the scientific procedures I can say nothing. To me, the instruments of geologists are arcane, their ideas strange – if beguiling, and their vocabulary foreign.
But, I am a clinician, knowledgeable about kidney stones more than most people. So, though I know nothing about their techniques, I can understand how their work might affect clinical practice, and paraphrase that aspect of the work for all who read here.
As well, many of their core findings – that crystals can dissolve within a tiny region of a stone and its constituent calcium and oxalate reform into another crystal, and that the many proteins in urine affect crystals – are well known and have been studied for decades. I have published research on many of these so called crystal inhibitors.
The Objects They Studies
Stones Collected from Six Patients
The Patients were Overweight, Hyperglycemic, and Hypercalciuric
They were given stones from 6 patients (2 males) who underwent percutaneous stone removal at Mayo Clinic. They were overweight or obese; two had diabetes, while ‘most’ of the rest (4) had high blood glucose concentrations – mean=125 ml/dl). All six were hypercalciuric with a mean 24 hour calcium excretion of 353 mg. Oxalate excretions were normal.
These are in one way commonplace stone patients. They formed calcium oxalate stones and had high urine calcium excretions. The latter was presumably idiopathic hypercalciuria, although the two diabetics may have had an additional cause. Urine supersaturation with respect to calcium oxalate was indeed high.
In other ways they are not at all typical. That all 6 had abnormally high blood glucose levels whose mean measured 125 mg/dl stands out in that the average stone patient is not routinely hyperglycemic. Likewise for their high body weight and that 2/6 were frankly diabetic and, of course, that female sex predominated whereas overall men predominate in calcium oxalate stone forming populations.
In other words, the six patient Mayo Clinic cohort did not well ‘…represent the profile of risk factors and comorbidities expected in a cohort of recurrent calcium oxalate stone formers.’ (Supplemental materials, part 1). They come from what is best called a rather unusual cohort – especially in their high stone burden necessitating PNL, and their abnormal blood glucose levels.
The Stone Burden Was Unusually Large
Most stone surgery is not percutaneous nephrolithotomy (PNL) because most patients do not have such large numbers of stones, or such large stones as to warrant it. Rather, the usual is ureteroscopic stone removal or, especially in past eras, shock wave lithotripsy.
The large stone burdens are in the calyces and renal pelvis, so it is not surprising that the authors found that stones formed free floating, as in the sediments of streams and rivers, or perhaps caves. Small attached stones hardly would have warranted PNL.
Only One Stone Fragment Was Presented in Detail
Of the 50 fragments harvested from the 6 PNL cases, one (labeled MP2) contained all of the events of interest, and it is data from that one fragment that provides the basis for the data presentation in the paper. However, one assumes that all of the fragments were indeed studied and displayed similar phenomena.
They Used Calcium Carbonate Crystals as Contrast
As a kind of contrast, the authors studied a calcium carbonate stalagmite from a cave, and travertine (another form of calcium carbonate) from a Roman aqueduct.
What They Found
Crystals in Stones Dissolve
Although the emphasis throughout the paper is on dissolution of kidney stone crystals, what they actually describe is more nuanced and includes both dissolution and reformation. Of course, given the massive stone burdens that led to PNL, the stone mass was growing larger and larger over the months and years in each patient. So local crystal dissolution had to be balanced not only by equal new crystal formation but by overall new crystal formation and growth throughout the stones.
Organic Molecules Play a Role
In Maintaining a Supersaturated Urine
As stone scientists have known for decades, crystals in stones are coated by a mix of organic molecules – proteins, for example – that affect their growth, aggregation, nucleation – so called ‘macromolecular inhibitors’. Many attempts to employ this knowledge have failed to yield diagnostic significance, and so far no one has attempted to use such molecules medically.
Of the many clinical studies of inhibitors, I reviewed two of my own – done with many collaborators far more skilled than I – that concluded that two small molecules, citrate and inorganic pyrophosphate, may account for much of the ability of urine to maintain supersaturation without collapsing into crystal formation. This article is useful here as a link as its references give access to a range of other similar studies.
In Controlling Stability of Stone Crystals
Although most of us who have worked in kidney stone science do not know how to do such work, the present paper and others referenced there make clear that large molecules coating stone crystals can affect whether they dissolve or not.
That is the main significance of the paper I have chosen to review. Using methods far beyond anything I can understand, the authors show that inside the stone fragment they studied in great detail tiny crystals are forever dissolving and reforming, shifting from calcium oxalate dihydrate to monohydrate. They live in a dynamic and alterable world.
What They Mean to Say
These molecules offer a key to stone dissolution. If one could manipulate their concentrations and properties in the right way one could in principle get stones to dissolve. That is the new paradigm mentioned in their abstract, and the basis for the excellent NYT summary of what benefits might accrue from the work.
I Wrote to the First Author
Being as I am ignorant about the complex methods in the paper, I emailed the first author, Dr Mayandi Sivaguru, asking about the prospects of dissolving kidney stones:
‘Given that urine is supersaturated with respect to the calcium oxalate crystals involved, can you tell me in overall terms how the oxalate and calcium in the crystals are essentially pumped into the urine against a rather signiﬁcant free energy barrier? I understand local crystal dissolution from one phase and coupled reformation into another as a kind of pawn takes pawn traﬃcking of the calcium and oxalate, but to dissolve the crystals one eventually needs to get their atom and molecule into the solu on phase.’
His reply was complex as one wants from a fine scientist, but its gist was this:
‘To your first question, We don’t know the exact answer yet. But based on the presented results in our paper and literature analyzed, we believe that the urine in the kidney and kidney stones are not always in a static saturation state (urine) and the stones not from a start point of A to D in a linear manner. Rather it seems that it is a very dynamic reactor and lots of factors, especially, biological factors such as inhibitors, human and microbial derived macromolecules, control supersaturation, mineralization, dissolution, and recrystallization. That is why it could not be simply explained simply by laws of thermodynamics based on pure physical and chemical factors alone.’
The Senior Author Wrote to Me
Dr Bruce Fouke wrote an email clarifying what the research implied, and we had several interchanges. On my side was a perhaps boring insistence to know how stone crystals could in fact dissolve into the supersaturated urine we all produce. On his was a more complex response about the power that large molecules have to disrupt crystals.
I felt as if our two fields – clinical stone research and fundamental geological science – have distinctly different vocabularies and scientific metaphors, so that my question was not so much naive as misdirected, and his answers sophisticated but somehow not directly responsive to my question. That is a good thing. Science is all dapple and variegate. Each scientist has perhaps a few dozen real peers. Languages and assumptions are particular in each compartment. Ultimately, with time, enlightenment on both sides arises from translation.
We agreed, after several email exchanges, that the following quote I lifted from his writing well summarizes his view about the long term benefits of the research:
‘Characterization of the content and distribution the nano-layered organic matter-rich CaOx and determination of the specific mechanistic roles it plays in driving CaOx dissolution as a result of surface chemistry are the next necessary steps toward developing clinical interventions.’
He agreed that my final summary comment:
‘…this quote (the one above) means that in the future if the work goes well there may be eventual new ways to dissolve stones.’
What I Mean to Say
There Are No Present New Benefits for Patients
As you read on the web about ‘stone breakers’, new remedies to dissolve stones, and similar ads, do not believe that this arcane and rather elegant work implies that such remedies presently exist. It is easy to read about a new paper of high quality promising stone dissolution and believe, therefore, that remedies offering dissolution have a scientific base.
They do not at this time.
There are no remedies based on this excellent new work.
Nor are there any from the past.
Calcium oxalate stones cannot be dissolved inside of people by any drug or remedy presently available. They can be fractured with shock waves, or by lasers, as we have known about for decades, but not dissolved.
The authors, as they speak for themselves and as I summarize with their approval, promise only that their science, in the long run, may come up with something good for patients.
Their Work May Be More Limited Than It Appears
The stones they used came from open surgery, meaning from a much larger stone burden than one usually encounters. Instead of growing on plaque or over plugs, these stones accumulated in the calyces and renal pelvis and grew like sedimentary rocks bathed in urine. Perhaps their interior remodelling is like the more common stones, perhaps not.
If this new work does not apply to the common smaller stones, clinical value will be very limited. Very large stone burdens are not likely to dissolve no matter how elegant the treatment. It is the smaller stones where we have a chance. So it should be repeated with stones harvested from more representative cases.
The Path to the Clinic is Obscure
It is behovely to speak of manipulating the large molecules in urine, but something altogether different to actually do it. How? We do not know what regulates them, and we do not know which of the massive numbers of them actually matters. It may be that many play a role, each one a tiny role at that so we need to alter ensembles.
To speak of drug models of protein motifs, as one surely will think about, likewise poses serious problems. If crystal active and absorbed into the blood, any such crystal active drugs can reach the bone mineral and possibly affect bone formation or dissolution.
Our field is fortunate to have some new scientists come in with radically new methods and ideas. That is the way science can progress. If I were not a critic, what would be my purpose as a worker on this Earth. But a critic can be the best audience, the most appreciative, too.
I personally love the research, and wish these new visitors to our small world all happiness and success. Perhaps I am too pessimistic about eventual benefits to patients. I am old, and the old often mistake the future for having too much of a past.