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Randall’s plaque and calcium oxalate stone formation: role for immunity and inflammation

Nature Reviews Nephrology volume 17, pages 417–433 (2021)Cite this article

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Abstract

Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall’s plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular calcification, Randall’s plaques consist of calcium phosphate crystals mixed with an organic matrix that is rich in proteins, such as inter-α-trypsin inhibitor, as well as lipids, and includes membrane-bound vesicles or exosomes, collagen fibres and other components of the extracellular matrix. Kidney tissue surrounding Randall’s plaques is associated with the presence of classically activated, pro-inflammatory macrophages (also termed M1) and downregulation of alternatively activated, anti-inflammatory macrophages (also termed M2). In animal models, crystal deposition in the kidneys has been associated with the production of reactive oxygen species, inflammasome activation and increased expression of molecules implicated in the inflammatory cascade, including osteopontin, matrix Gla protein and fetuin A (also known as α2-HS-glycoprotein). Many of these molecules, including osteopontin and matrix Gla protein, are well known inhibitors of vascular calcification. We propose that conditions of urine supersaturation promote kidney damage by inducing the production of reactive oxygen species and oxidative stress, and that the ensuing inflammatory immune response promotes Randall’s plaque initiation and calcium stone formation.

Key points

  • Randall’s plaques contain calcium phosphate (CaP) crystals mixed with membranous vesicles, collagen fibres and molecules involved in inflammatory responses, such as osteopontin and inter-α-trypsin inhibitor.

  • Calcification is modulated by many macromolecules that are generally involved in inflammation and osteogenesis; these molecules are also highly expressed in the kidneys of stone formers and in experimental models of nephrolithiasis.

  • Exposure of the kidney epithelium to crystals induces the production of reactive oxygen species that activate the NOD-, LRR- and pyrin domain-containing protein 3 inflammasome; inhibition of reactive oxygen species production and inflammasome activation reduces crystal deposition in animal models.

  • In rodent models, the inflammatory response to interstitial crystal deposition attracts macrophages, which leads to giant cell formation and may eventually result in crystal elimination.

  • Gene expression studies of kidneys from patients with kidney stones revealed pro-inflammatory macrophage gene signatures, whereas genes characteristic of anti-inflammatory macrophages were less abundant.

  • A better understanding of inflammasome activation and modulation of immune response to urine supersaturation and crystal deposition may provide new therapeutic options to reduce kidney stone recurrence.

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Fig. 1: Kidney papilla with Randall’s plaque and plug.
Fig. 2: Composition of Randall’s plaque in the kidney papilla.
Fig. 3: Calcium phosphate deposits in animal models.
Fig. 4: Proposed effects of reactive oxygen species production in response to intratubular crystals.
Fig. 5: Proposed model for the formation of Randall’s plaque.

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Authors and Affiliations

  1. Department of Pathology, University of Florida, Gainesville, FL, USA

    Saeed R. Khan

  2. Department of Urology, University of Florida, Gainesville, FL, USA

    Benjamin K. Canales & Paul R. Dominguez-Gutierrez

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S.R.K. and P.R.D.-G. researched data for the article. All authors made substantial contributions to discussions of the content, wrote the manuscript, and reviewed or edited the manuscript before submission.

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B.K.C. receives grant support through Alnylam Pharmaceuticals and the National Institutes of Health, is paid for his services on the AUA Content Review Committee and has ownership/stock options with AP LifeSciences and ForTec Litho, LLC. The other authors declare no competing interests.

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Glossary

Lithogenic

Mineralization-inducing.

Concretions

Masses formed by the accumulation and aggregation of crystals.

Ectopic mineralization

A pathological biomineralization that occurs in soft tissue and generally involves the deposition of calcium phosphate.

Matrix vesicles

Small, membrane-bound and mostly spherical bodies present at mineralization sites.

Crystal nucleation

The first step of crystal formation in which ions reorganize to form a solid phase.

Transwell culture system

Culture system with two chambers separated by a permeable membrane that is used to investigate the role of soluble mediators in interactions between cells.

Giant cells

Multinucleated cells formed by the fusion of several distinct cells such as macrophages.

Medullary sponge kidney

A rare congenital kidney disorder in which small cysts form in the kidney tubules.

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Khan, S.R., Canales, B.K. & Dominguez-Gutierrez, P.R. Randall’s plaque and calcium oxalate stone formation: role for immunity and inflammation. Nat Rev Nephrol 17, 417–433 (2021). https://doi.org/10.1038/s41581-020-00392-1

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