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The role of macromolecules in the formation of kidney stones

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Abstract

The formation of crystal aggregates, one of the critical processes in kidney stone pathogenesis, involves interactions between crystals (predominantly calcium oxalate monohydrate, COM) and urinary constituents (e.g., proteins), which serve as an adhesive “glue” between crystals in stones. To develop a better understanding of the protein–crystal interactions that lead to crystal aggregation, we have measured the effect of model proteins on bulk COM crystal properties as well as their adsorption on crystal surfaces using three synthetic polyanions: poly(aspartic acid) (polyD), poly(glutamic acid) (polyE), and poly(acrylic acid) (polyAA). These anionic macromolecules reduced the amount of COM crystal aggregation in bulk solution to an extent similar to that observed for mixture of proteins from normal urine, with little difference between the polymers. In contrast, the polymers exhibited differences in measures of COM crystal growth. Polycations such as poly(arginine) (polyR) and poly(lysine) (polyK) reduced aggregation weakly and exerted negligible effects on crystal growth. All polyions were found to associate with COM crystal surfaces, as evidenced by changes in the zeta potential of COM crystals in electrophoretic mobility measurements. On the other hand, COM aggregation and possibly growth can be promoted by many binary mixtures of polycations and polyanions, which appeared to be mediated by polymer aggregate formation rather than loss of crystal charge stabilization. Similarly, crystal aggregation promotion behavior can be driven by forming aggregates of weakly charged polyanions, like Tamm–Horsfall protein, suggesting that polymer (protein) aggregation may play a critical role in stone formation. Sensitivity of polyanion–COM crystal surface interactions to the chemical composition of polymer side groups were demonstrated by large differences in crystal aggregation behavior between polyD and polyE, which correlated with atomic force microscopy (AFM) measurements of growth inhibition on various COM surfaces and chemical force microscopy (CFM) measurements of unbinding forces between COM crystal surfaces and AFM tips decorated with either carboxylate or amidinium moieties (mimicking polyanion and polyR side chains, respectively). The lack of strong interaction for polyE at the COM (100) surface compared to polyD appeared to be the critical difference. Finally, the simultaneous presence of polyanions and polycations appeared to alter the ability of polycations to mediate unbinding forces in CFM and promote crystal growth. In summary, polyanions strongly associated with COM surfaces and influenced crystallization, while polycations did not, though important differences were observed based on the physicochemical properties of polyanions. Observations suggest that COM aggregation with both polyanion–polycation mixtures and weakly charged polyanions is promoted by polymer aggregate formation, which plays a critical role in bridging crystal surfaces.

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Acknowledgements

We gratefully acknowledge the financial support provided by the Department of Veterans Affairs through their Research Career Development and Merit Review Programs (RCD and MR 9305 JAW) and in part with resources and the use of facilities at the Clement J. Zablocki Department of Veterans Affairs Medical Center, Milwaukee, WI. Funding was also obtained through parts of several grants from the National Institutes of Health/National Institute for Diabetes, Digestive, and Kidney Diseases (DK 68551, 74741, and 82550-JAW). Additional financial support was provided by the Medical College of Wisconsin Jacob Lemann Endowment Grant, the Materials Research Science and Engineering Center (MRSEC) program of the National Science Foundation under Award Number DMR-1420073 (MDW), the Welch Foundation under Award Number E-1794 (JDR), and the National Science Foundation under Award Number 1207441 (JDR). We also gratefully acknowledge the technical support from MIS.MAC (Mandel International Stone and Molecular Analysis Center), Milwaukee, WI, for crystal analysis through Dr. Neil Mandel, as well as particular contributions from Dr. William Zachowicz to ζ-potential measurements and Samuel Cohen to polyanion–polycation aggregation experiments.

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of Houston, 4726 Calhoun Rd, Houston, TX, 77204-4004, USA

    Jeffrey D. Rimer

  2. Department of Medicine/Nephrology Division, The Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI, 53226, USA

    Ann M. Kolbach-Mandel

  3. Department of Chemistry and the Molecular Design Institute, New York University, 100 Washington Square East, New York, NY, 10003-6688, USA

    Michael D. Ward

  4. Department of Medicine/Nephrology Division, Department of Veterans Affairs Medical Center, The Medical College of Wisconsin, 5000 West National Avenue, Milwaukee, WI, 53295, USA

    Jeffrey A. Wesson

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  1. Jeffrey D. Rimer
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  2. Ann M. Kolbach-Mandel
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  4. Jeffrey A. Wesson
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Correspondence to Jeffrey A. Wesson.

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Funding

This study which spanned many years was funded with grants for the Department of Veterans Affairs Career Development and Merit Review programs (RCD and MR 9305 - JAW) and the use of facilities at the Clement J. Zablocki Department of Veterans Affairs Medical Center, Milwaukee, WI, and in part by grants from the National Institutes of Health (NIDDK, DK 68551, 74741, and 82550 - JAW). Additional financial support was provided by the Medical College of Wisconsin Jacob Lemann Endowment Grant and the Materials Research Science and Engineering Center (MRSEC) program of the National Science Foundation under Award Number DMR-1420073 (MDW).

Human studies

The participating patient in this study was recruited with informed consent to an established study under VA IRB approval (VA-IRB Protocol: 9305-01P). All procedures performed in these studies were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments.

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Submitted to Special Issue of Urolithiasis on the “Physico-chemical, Biochemical and Biological Mechanisms of Stone-Formation” November 24, 2016.

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Rimer, J.D., Kolbach-Mandel, A.M., Ward, M.D. et al. The role of macromolecules in the formation of kidney stones. Urolithiasis 45, 57–74 (2017). https://doi.org/10.1007/s00240-016-0948-8

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