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  • Review Article
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Human kidney stones: a natural record of universal biomineralization

Nature Reviews Urology volume 18, pages 404–432 (2021)Cite this article

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Abstract

GeoBioMed — a new transdisciplinary approach that integrates the fields of geology, biology and medicine — reveals that kidney stones composed of calcium-rich minerals precipitate from a continuum of repeated events of crystallization, dissolution and recrystallization that result from the same fundamental natural processes that have governed billions of years of biomineralization on Earth. This contextual change in our understanding of renal stone formation opens fundamentally new avenues of human kidney stone investigation that include analyses of crystalline structure and stratigraphy, diagenetic phase transitions, and paragenetic sequences across broad length scales from hundreds of nanometres to centimetres (five Powers of 10). This paradigm shift has also enabled the development of a new kidney stone classification scheme according to thermodynamic energetics and crystalline architecture. Evidence suggests that ≥50% of the total volume of individual stones have undergone repeated in vivo dissolution and recrystallization. Amorphous calcium phosphate and hydroxyapatite spherules coalesce to form planar concentric zoning and sector zones that indicate disequilibrium precipitation. In addition, calcium oxalate dihydrate and calcium oxalate monohydrate crystal aggregates exhibit high-frequency organic-matter-rich and mineral-rich nanolayering that is orders of magnitude higher than layering observed in analogous coral reef, Roman aqueduct, cave, deep subsurface and hot-spring deposits. This higher frequency nanolayering represents the unique microenvironment of the kidney in which potent crystallization promoters and inhibitors are working in opposition. These GeoBioMed insights identify previously unexplored strategies for development and testing of new clinical therapies for the prevention and treatment of kidney stones.

Key points

  • Data from an emerging field, GeoBioMed, show that human kidney stone formation is controlled by the same fundamental sequence of processes that governs phosphate, carbonate and silicate deposition in other natural and engineered environments on Earth, which are known as universal biomineralization and diagenetic phase transitions.

  • Human kidney stones classified as ‘apatite’, ‘COD’ (calcium oxalate dihydrate), ‘COM’ (calcium oxalate monohydrate), or simply ‘CaOx’ (calcium oxalate) are actually composed of multiple mineralogical components (none is 100% purely one mineral) that comprise the continuum of diagenetic phase transitions from which they formed, which include amorphous calcium phosphate (ACP), hydroxyapatite (HAP), COD and COM.

  • ACP and HAP spherules grow, cluster and coalesce to form euhedral COD crystals with planar concentric zoning and sector zones, indicating disequilibrium precipitation from supersaturated urine.

  • ACP, HAP, COD and COM nanolayering and cross-cutting crystalline relationships (for example, dissolution voids, fracturing and faulting) record a complete stratigraphic record and paragenetic sequence that is analogous to natural and engineered biomineralization and diagenetic phase transition systems, the only difference being time and scale.

  • At least 50% of the total volume of whole and fragmented kidney stones has naturally undergone repeated events of in vivo dissolution and recrystallization.

  • This approach has revealed multiple testing targets for the development of new clinical therapies, which includes growth of kidney stones within GeoBioCell microfluidic testbeds during control of key parameters, such as gradients and fluctuations in urine solution chemistry, changing flow, protein and small-molecule concentrations, and microbiome composition.

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Fig. 1: Universal biomineralization and diagenetic phase transitions.
Fig. 2: A newly synthesized classification scheme based on diagenetic phase transitions in human kidney stones.
Fig. 3: Diagenetic phase transition of ACP and HAP spherules to planar concentric zonations and sector zones.
Fig. 4: Diagenetic phase transition of ACP and HAP spherules to planar concentric zonations and sector zones in COD.
Fig. 5: Diagenetic phase transitions of ACP spherules to planar concentric zonations and sector zones in human kidney stone COD and geode quartz (agate).
Fig. 6: Thin section of a HAP, COD and COM human kidney stone fragment.
Fig. 7: Fracturing, faulting, repeated bulk dissolution and recrystallization of a HAP, COD and COM human kidney stone.
Fig. 8: The paragenetic sequence of ACP, HAP, COD and COM human kidney stone formation.
Fig. 9: Comparison of layering in natural systems, from a macro to micro to nano-scale.
Fig. 10: Comparison of high-frequency planar concentric nanolayering in dolomite crystals and in ACP, COD and COM human kidney stones.

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Acknowledgements

This research was supported by the Mayo Clinic and University of Illinois Strategic Alliance for Technology-Based Healthcare, the Mayo Clinic Center for Individualized Medicine, the Mayo Clinic O’Brien Urology Research Center (no. DK100227), the Mayo Nephrology/Urology Summer Undergraduate Research Fellowship (nuSURF; no. DK101405), and the National Aeronautics and Space Administration (NASA) Astrobiology Institute (Cooperative Agreement no. NNA13AA91A) issued through the Science Mission Directorate. The authors thank Charles J. Werth for ongoing invaluable scientific discussions and detailed editing, as well as Tom Shearer for providing high-resolution imaging and sample collection information on agate geodes.

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Authors and Affiliations

  1. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Mayandi Sivaguru, Jessica J. Saw, Elena M. Wilson & Bruce W. Fouke

  2. Carl Zeiss Labs@Location Partner, Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Mayandi Sivaguru & Bruce W. Fouke

  3. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Jessica J. Saw

  4. Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, USA

    Jessica J. Saw

  5. School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Elena M. Wilson & Bruce W. Fouke

  6. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    John C. Lieske & Michael F. Romero

  7. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    John C. Lieske

  8. Department of Urology, Mayo Clinic, Rochester, MN, USA

    Amy E. Krambeck

  9. Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

    Amy E. Krambeck

  10. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    James C. Williams & Nicholas Chia

  11. Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Michael F. Romero

  12. Jackson School of Geosciences, University of Texas at Austin, Austin, TX, USA

    Kyle W. Fouke

  13. Carl Zeiss Microscopy LLC, One North Broadway, White Plains, NY, USA

    Matthew W. Curtis & Jamie L. Kear-Scott

  14. Department of Individualized Medicine, Mayo Clinic, Rochester, MN, USA

    Nicholas Chia

  15. Department of Geology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Bruce W. Fouke

  16. Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Bruce W. Fouke

  17. Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    Bruce W. Fouke

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  1. Mayandi Sivaguru
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Contributions

M.S., J.J.S., E.M.W., J.C.L., A.E.K., J.C.W., M.F.R., K.W.F., M.W.C., J.L.K.-S. and B.W.F. researched data for the article. M.S. and B.W.F. made substantial contributions to discussions of content and wrote the manuscript. All authors reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Mayandi Sivaguru or Bruce W. Fouke.

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Competing interests

The Microscopy Facility at the Carl R. Woese Institute for Genomic Biology, University of Urbana-Champaign, is a Carl Zeiss Labs @ Location Partner and has a priority access “before market” agreement for Carl Zeiss Microscope systems for testing, evaluation and reporting. The authors declare no competing interests.

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High resolution main figures and supplementary figures link: https://figshare.com/s/9277572cd07d0be5bc9d

Supplementary information

Glossary

Biomineralization

The processes and products of mineral precipitation that are influenced by the ThreeDomains of Life.

Diagenetic phase transitions

Sequential direct and step-wise events of crystal precipitation, dissolution and reprecipitation.

GeoBioMed

A new transdisciplinary convergence approach that integrates cutting-edge technologies and fundamental governing principles in geology and biology (geobiology) with those in medicine.

Fourier transform infrared spectroscopy

Used to determine the mineralogical composition of a crystal or stone.

Super-resolution autofluorescence microscopy

(SRAF). Blue (405 nm), green (488 nm) and red (561 nm) laser excitation wavelengths, which generate blue (410–480 nm), green (500–550 nm) and red (575–615 nm) light emission wavelengths that can be detected at an average spatial resolution of 140 nm.

Powers of 10

A contextualization system with which to make comparisons over small to large spatial and temporal scales, with relative dimensions described using exponential notations of the number 10.

Gibbs free energy

Originally described as “available energy” by Josiah Willard Gibbs in 1873, this parameter characterizes the thermodynamic nature of any given system. It is the total energy available to execute a given reaction under constant temperature and pressure.

Solubility product

(Ksp). A quantitative thermodynamic evaluation of whether minerals will precipitate or dissolve in solution based primarily on the relative concentration of dissolved ions and temperature.

Bipyramid

A structural category of crystalline solids that is composed of two pyramid-shaped structures that are flipped mirror images of each other joined at the base (for example, calcium oxalate dihydrate).

Monoclinic

A structural category of crystalline solids that has three axes of unequal lengths, one of which is perpendicular to the other two (for example, calcium oxalate dihydrate).

Anhedral crystals

Crystals that have grown to form irregular-shaped faces.

Euhedral crystals

Crystals that have grown to form perfect geometrically shaped faces.

Sector zones

Individual age-equivalent crystal faces exhibit differences in the rate of incorporation of ions and biomolecules, including organic matter, independent of the bulk urine chemistry at the time of crystallization.

Ostwald’s rule

Crystals evolve through a series of phase transitions that progress towards the smallest loss of free energy, transitioning from less thermodynamically stable to more stable polymorphs. The first type is Ostwald ripening, where spherules merge, coalesce and increase in size but maintain their original shape. The second type is Ostwald coalescence, where spherules of similar sizes laterally aggregate and eventually form a planar surface.

Paragenetic sequence

The entire history of diagenetic phase transitions that have formed crystalline stone deposits. These result from the physical, chemical and biological processes active within the environment of deposition.

Mold

An original crystal that was entombed by another crystal or crystal aggregate, which was then fully dissolved, leaving a void space in the shape of the original crystal (also called moldic porosity).

Calvin cycle

A process that plants use to transform carbon dioxide into sugar.

GeoBioCell

A custom designed and constructed microfluidic bioreactor in which the interaction between urine at variable states of saturation, renal microorganisms, stone fragments and many other relevant kidney parameters can be tracked under highly controlled environmental conditions.

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Sivaguru, M., Saw, J.J., Wilson, E.M. et al. Human kidney stones: a natural record of universal biomineralization. Nat Rev Urol 18, 404–432 (2021). https://doi.org/10.1038/s41585-021-00469-x

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