GeoBioMed: How geologic rock formations inform novel treatments for kidney stones – Part I


Communique

Human kidney stones are at least as old as the Giza pyramids. The oldest known kidney stone was found in Egyptian burial satin from 4400 B.C. In 2020, Mayo Clinic processed and analyzed some 90,000 kidney stones from all over the world. That number increases each year, reflecting a global uptick in kidney stone disease. But new research has unlocked how kidney stones actually form, which could be the key to treating or even eliminating this often-painful condition. 

About three years ago, an interdisciplinary, collaborative study between Mayo Clinic and the University of Illinois debunked the consensus that kidney stones grow in a methodical, layer-by-layer process and are hard to dissolve. “It’s been thought that, once they grow and develop, you’re not going to dissolve the calcium kidney stones under conditions that would typically be found in your kidney,” says John Lieske, M.D., nephrologist and director of Mayo Clinic’s Rare Kidney Stone Consortium, who co-leads the team.

John Lieske, M.D., nephrologist and director of Mayo Clinic’s Rare Kidney Stone Consortium

Contrary to this longtime belief, the study found that calcium oxalate kidney stones form much the same way as travertine, a rock found in Mammoth Hot Springs of Yellowstone National Park. In other words, kidney stones, like rocks formed in natural environments, “undergo previously unforeseen cycles of repeated crystallization, dissolution, fracturing and faulting.” This process of post-formational physical, chemical, and biological alteration is called diagenesis.

The discovery opens the way for new, unorthodox treatments for kidney stones, and was possible by joining University of Illinois’ geology and biology (geobiology) forces with Mayo’s urology and nephrology expertise. The new approach is known as GeoBioMed.

For the study, kidney stone samples surgically removed from Mayo patients had to be cut into sections as thin as rice paper. “We cut them so thin that you can shine light through them,” says Bruce Fouke, Ph.D., geobiologist and director of the Roy J. Carver Biotechnology Center, whose laboratories at the University of Illinois have the specialized tools for the job. “When you hit a kidney stone, cut very thinly, with UV light and view it through a microscope — on a scale of one-millionth to one-billionth of a meter — you see that there are layers upon layers of individual, very perfectly shaped crystals, which are cross-cut by other crystals, dissolved holes, fractures and faults. This provides astounding photographic imagery.”

 (Left to right) Jessica Saw, medical student, Bruce Fouke, Ph.D., and Mayandi Sivaguru, Ph.D., all of whom worked on this project at the University of Illinois.

“They are very similar to what you see when you stand on the edge of the Grand Canyon, where you have striking rock layering. Rock layers at the bottom are older than the rock layers at the top, which record a complex detailed history of deposition, dissolution, faulting, and other forms of alteration. We see the exact same process, but on a micro-scale, within human kidney stones.”

The finding was so significant The New York Times featured it as hot medical/nature news. That’s because the implications of the study include new treatment protocols that could, for example, interrupt a stone’s formation or encourage the dissolution stage. This is good news given that a lodged stone can be more painful than childbirth, according to some women who have experienced both.

A new classification scheme

According to the team’s latest paper, published in Nature Reviews Urology, the ongoing study has made further breakthroughs toward that goal. Researchers have established a new classification scheme, which gives doctors a way to classify kidney stones into different unique categories independent of knowing precisely where the stones form within the kidney. 

“This was initially a huge hurdle to overcome because, along with John’s team at Mayo, we had to first wade through the existing terminology,” says Dr. Fouke, who travels the world exploring coral reefs, hot springs, cave formations, and other natural systems to study how living organisms interact with rocks and water. “A serious scientific study demands that the results be both reproducible and accurately predictive. To achieve this, you need to start by developing a way to describe what you are looking at without making initial biased interpretations. Therefore, having a way to classify stones, without hypothetical interpretation of where the stone may or may not have formed in the kidney, has been critical.

“Finally, after five years, we said, ‘OK, look, previous work has shown that there are a multitude of different types of kidney stones.’ Then, once we got all the previous observations on the table, we could start conducting our own systematic scientific tests."

“With this latest paper, we have constructed this new classification scheme without preordained interpretation, and this has allowed us to establish this progressive new approach for kidney stones,” says Dr. Fouke.    

The classification scheme was put through a rigorous proof-of-concept evaluation, incorporating chemical energy and diagenetic alteration of the system within the human kidney. This was done to contextualize the physical, chemical, and biological processes controlling how stone formation is taking place.

When kidney stone are cut very thinly, illuminated with UV light, and viewed through a microscope, parallels with naturally forming crystals can been distinguished.

“And it’s not just mineral growth, but also a complexity of ongoing, multiple events of crystallization and dissolution, crystallization and dissolution,” says Dr. Fouke. “When a stone goes through the dissolving stage, it doesn’t dissolve completely. A stone grows and then only partially dissolves during each one of these cycles. It looks a little like swiss cheese. You leave some of the mineral mass behind that contains previous crystals, holes, fractures, and faults in it. Then more mineral growth, dissolution, fracturing, and faulting takes place in the next sequence, and so on. We’ve now documented, quantitatively, this series of steps into a stone formation history called a paragenetic sequence.”

Researchers found that, remarkably, the human kidney naturally removes more than 50 percent, by volume, of the original stone mass during the dissolving series of steps. This marked the first qualitative proof that the majority of the total volume of whole and fragmented kidney stones have undergone repeated events of in vivo dissolution and recrystallization.

Kidney stones undergo “superfast” layering

Among a host of breakthrough findings, the paper details how human kidney stone formation is controlled by “the same fundamental sequence of processes that govern mineral deposition in other natural and engineered environments on Earth through geological time,” says Jessica Saw, a medical student at Mayo Clinic Alix School of Medicine and former Ph.D. student in Dr. Fouke’s lab. “When a stone or rock is growing, there is the rate of crystallization versus frequency of layering.”

In other words, the fundamental mechanisms by which a stone forms in the kidney are analogous to natural systems such as hot springs, caves and coral reefs. The growth of biologically influenced minerals in natural systems, called universal biomineralization, has been going on for four billion years.

These same basic principles are now being utilized by NASA’s Perseverance Rover on Mars to search for rocks composed of ancient, layered microbial life in deposits called stromatolites. But human kidney stones undergo a much higher frequency of layering than any layered rock or mineral deposits previously seen in nature.

“We have been using the same tool kit on kidney stones that we use to understand how corals respond to rapid increases in sea surface temperatures during global warming,” says Dr. Fouke.  “The rate of crystal growth in many natural environments is sometimes much faster than what we see in kidney stones. However, the frequency of crystalline and organic layering exhibited in kidney stones is much faster than anything previously seen in natural systems. These GeoBioMed perspectives are why it has been challenging for the medical world to get their head around how kidney stones form.

“The medical sciences look at stones from a medical perspective, which of course has its own incredible depth and expertise. But this doesn’t include a historical contextual insight into time and space during mineralization as established by universal biomineralization. Equally important is that geobiologists don’t have training in physiology, biochemistry and disease development, and this is vital to understanding kidney stone growth. The exciting part is that medical doctors and geobiologists now have the opportunity to mutually inform and support each other to better understand fundamental parameters, such as rate of mineral growth versus frequency of layering, and the relative magnitude and influence of each.” In Mammoth Hot Springs, the rate of crystal deposition of travertine rocks is a million to a billion times faster than most other limestones that form on the planet’s surface. This explains why more than one ton of travertine is deposited per day at this site: microbial bacteria in the hot springs make proteins and other molecules that allow the rocks to grow extremely quickly. Similar proteins also are created in the kidney, both by the human host and the resident microorganisms (aka microbiome). The difference is the kidney tries to “defend” itself against and decrease or halt stone formation, whereas nature allows this layering process that promotes rock growth.

The Pleistocene-aged travertine formed in Italian hot springs identical to those in which terraced travertine is currently being deposited at Mammoth Hot Springs in Yellowstone National Park. This rock is used on the floors and wall facings in the Gonda Building.

“What’s been over-the-top exciting about our work with Mayo is the finding that there is no other natural system on the planet like the kidney, and the formation of kidney stones,” says Dr. Fouke. “We’re talking about the deepest ocean, the highest mountain, ice sheets in the Antarctic, deep underground caves. There’s nowhere on Earth that we’ve ever found stones that grow a layering pattern, a stratigraphy, at the rates and with the beautiful resolution, that you have in kidney stones.”           

Why does the human kidney stone have a much faster layering rate than anything in nature?

Dr. Fouke explains it this way: “The kidney has inhibitors, because the human body is trying to fight this mineral growth like crazy,” he says. “These inhibitors are in the form of biochemical compounds that the body is making — at the same time the whole complex human microbiome is fighting to survive. And so the reason you have such a high frequency of layering is you have all these impediments in the human body trying to stop the stone from growing, and so it ends up making layers. We have also shown that the microbiome becomes entombed and fossilized within the growing kidney stones. This raises yet another whole new set of questions regarding how the microbiome might either enhance or thwart stone growth, depending on the state of the kidney.”

To learn more on the clinical implications for this research, click here for Part II.

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Christoph Bahn (@cjbahnsen)

Christoph Bahn

Christoph Bahn covers emerging research and discovery for Mayo Clinic Laboratories. His writing has also appeared in The New York Times, Los Angeles Times, and Smithsonian Air & Space. He divides his time between Southern California and Northwest Ohio.