Unified theory on the pathogenesis of Randall’s plaques and plugs

Saeed R. Khan, Benjamin K. Canales

Research output: Contribution to journalArticle

Abstract

Kidney stones develop attached to sub-epithelial plaques of calcium phosphate (CaP) crystals (termed Randall’s plaque) and/or form as a result of occlusion of the openings of the Ducts of Bellini by stone-forming crystals (Randall’s plugs). These plaques and plugs eventually extrude into the urinary space, acting as a nidus for crystal overgrowth and stone formation. To better understand these regulatory mechanisms and the pathophysiology of idiopathic calcium stone disease, this review provides in-depth descriptions of the morphology and potential origins of these plaques and plugs, summarizes existing animal models of renal papillary interstitial deposits, and describes factors that are believed to regulate plaque formation and calcium overgrowth. Based on evidence provided within this review and from the vascular calcification literature, we propose a “unified” theory of plaque formation—one similar to pathological biomineralization observed elsewhere in the body. Abnormal urinary conditions (hypercalciuria, hyperoxaluria, and hypocitraturia), renal stress or trauma, and perhaps even the normal aging process lead to transformation of renal epithelial cells into an osteoblastic phenotype. With this de-differentiation comes an increased production of bone-specific proteins (i.e., osteopontin), a reduction in crystallization inhibitors (such as fetuin and matrix Gla protein), and creation of matrix vesicles, which support nucleation of CaP crystals. These small deposits promote aggregation and calcification of surrounding collagen. Mineralization continues by calcification of membranous cellular degradation products and other fibers until the plaque reaches the papillary epithelium. Through the activity of matrix metalloproteinases or perhaps by brute physical force produced by the large sub-epithelial crystalline mass, the surface is breached and further stone growth occurs by organic matrix-associated nucleation of CaOx or by the transformation of the outer layer of CaP crystals into CaOx crystals. Should this theory hold true, developing an understanding of the cellular mechanisms involved in progression of a small, basic interstitial plaque to that of an expanding, penetrating plaque could assist in the development of new therapies for stone prevention.

Original languageEnglish (US)
Pages (from-to)109-123
Number of pages15
JournalUrolithiasis
Volume43
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Kidney
Fetuins
Hyperoxaluria
Calcium
Vascular Calcification
Hypercalciuria
Osteopontin
Kidney Calculi
Crystallization
Matrix Metalloproteinases
Collagen
Epithelium
Animal Models
Epithelial Cells
Phenotype
Bone and Bones
Wounds and Injuries
Growth
calcium phosphate
Proteins

Keywords

  • Calcification
  • Calcium oxalate
  • Hydroxyapatite
  • Kidney stones
  • Randall’s plaque
  • Randall’s plug

ASJC Scopus subject areas

  • Urology

Cite this

Unified theory on the pathogenesis of Randall’s plaques and plugs. / Khan, Saeed R.; Canales, Benjamin K.

In: Urolithiasis, Vol. 43, No. 1, 2014, p. 109-123.

Research output: Contribution to journalArticle

Khan, Saeed R. ; Canales, Benjamin K. / Unified theory on the pathogenesis of Randall’s plaques and plugs. In: Urolithiasis. 2014 ; Vol. 43, No. 1. pp. 109-123.
@article{cc20eb88b8db4d8c91e37431734a8aad,
title = "Unified theory on the pathogenesis of Randall’s plaques and plugs",
abstract = "Kidney stones develop attached to sub-epithelial plaques of calcium phosphate (CaP) crystals (termed Randall’s plaque) and/or form as a result of occlusion of the openings of the Ducts of Bellini by stone-forming crystals (Randall’s plugs). These plaques and plugs eventually extrude into the urinary space, acting as a nidus for crystal overgrowth and stone formation. To better understand these regulatory mechanisms and the pathophysiology of idiopathic calcium stone disease, this review provides in-depth descriptions of the morphology and potential origins of these plaques and plugs, summarizes existing animal models of renal papillary interstitial deposits, and describes factors that are believed to regulate plaque formation and calcium overgrowth. Based on evidence provided within this review and from the vascular calcification literature, we propose a “unified” theory of plaque formation—one similar to pathological biomineralization observed elsewhere in the body. Abnormal urinary conditions (hypercalciuria, hyperoxaluria, and hypocitraturia), renal stress or trauma, and perhaps even the normal aging process lead to transformation of renal epithelial cells into an osteoblastic phenotype. With this de-differentiation comes an increased production of bone-specific proteins (i.e., osteopontin), a reduction in crystallization inhibitors (such as fetuin and matrix Gla protein), and creation of matrix vesicles, which support nucleation of CaP crystals. These small deposits promote aggregation and calcification of surrounding collagen. Mineralization continues by calcification of membranous cellular degradation products and other fibers until the plaque reaches the papillary epithelium. Through the activity of matrix metalloproteinases or perhaps by brute physical force produced by the large sub-epithelial crystalline mass, the surface is breached and further stone growth occurs by organic matrix-associated nucleation of CaOx or by the transformation of the outer layer of CaP crystals into CaOx crystals. Should this theory hold true, developing an understanding of the cellular mechanisms involved in progression of a small, basic interstitial plaque to that of an expanding, penetrating plaque could assist in the development of new therapies for stone prevention.",
keywords = "Calcification, Calcium oxalate, Hydroxyapatite, Kidney stones, Randall’s plaque, Randall’s plug",
author = "Khan, {Saeed R.} and Canales, {Benjamin K.}",
year = "2014",
doi = "10.1007/s00240-014-0705-9",
language = "English (US)",
volume = "43",
pages = "109--123",
journal = "Urolithiasis",
issn = "2194-7228",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Unified theory on the pathogenesis of Randall’s plaques and plugs

AU - Khan, Saeed R.

AU - Canales, Benjamin K.

PY - 2014

Y1 - 2014

N2 - Kidney stones develop attached to sub-epithelial plaques of calcium phosphate (CaP) crystals (termed Randall’s plaque) and/or form as a result of occlusion of the openings of the Ducts of Bellini by stone-forming crystals (Randall’s plugs). These plaques and plugs eventually extrude into the urinary space, acting as a nidus for crystal overgrowth and stone formation. To better understand these regulatory mechanisms and the pathophysiology of idiopathic calcium stone disease, this review provides in-depth descriptions of the morphology and potential origins of these plaques and plugs, summarizes existing animal models of renal papillary interstitial deposits, and describes factors that are believed to regulate plaque formation and calcium overgrowth. Based on evidence provided within this review and from the vascular calcification literature, we propose a “unified” theory of plaque formation—one similar to pathological biomineralization observed elsewhere in the body. Abnormal urinary conditions (hypercalciuria, hyperoxaluria, and hypocitraturia), renal stress or trauma, and perhaps even the normal aging process lead to transformation of renal epithelial cells into an osteoblastic phenotype. With this de-differentiation comes an increased production of bone-specific proteins (i.e., osteopontin), a reduction in crystallization inhibitors (such as fetuin and matrix Gla protein), and creation of matrix vesicles, which support nucleation of CaP crystals. These small deposits promote aggregation and calcification of surrounding collagen. Mineralization continues by calcification of membranous cellular degradation products and other fibers until the plaque reaches the papillary epithelium. Through the activity of matrix metalloproteinases or perhaps by brute physical force produced by the large sub-epithelial crystalline mass, the surface is breached and further stone growth occurs by organic matrix-associated nucleation of CaOx or by the transformation of the outer layer of CaP crystals into CaOx crystals. Should this theory hold true, developing an understanding of the cellular mechanisms involved in progression of a small, basic interstitial plaque to that of an expanding, penetrating plaque could assist in the development of new therapies for stone prevention.

AB - Kidney stones develop attached to sub-epithelial plaques of calcium phosphate (CaP) crystals (termed Randall’s plaque) and/or form as a result of occlusion of the openings of the Ducts of Bellini by stone-forming crystals (Randall’s plugs). These plaques and plugs eventually extrude into the urinary space, acting as a nidus for crystal overgrowth and stone formation. To better understand these regulatory mechanisms and the pathophysiology of idiopathic calcium stone disease, this review provides in-depth descriptions of the morphology and potential origins of these plaques and plugs, summarizes existing animal models of renal papillary interstitial deposits, and describes factors that are believed to regulate plaque formation and calcium overgrowth. Based on evidence provided within this review and from the vascular calcification literature, we propose a “unified” theory of plaque formation—one similar to pathological biomineralization observed elsewhere in the body. Abnormal urinary conditions (hypercalciuria, hyperoxaluria, and hypocitraturia), renal stress or trauma, and perhaps even the normal aging process lead to transformation of renal epithelial cells into an osteoblastic phenotype. With this de-differentiation comes an increased production of bone-specific proteins (i.e., osteopontin), a reduction in crystallization inhibitors (such as fetuin and matrix Gla protein), and creation of matrix vesicles, which support nucleation of CaP crystals. These small deposits promote aggregation and calcification of surrounding collagen. Mineralization continues by calcification of membranous cellular degradation products and other fibers until the plaque reaches the papillary epithelium. Through the activity of matrix metalloproteinases or perhaps by brute physical force produced by the large sub-epithelial crystalline mass, the surface is breached and further stone growth occurs by organic matrix-associated nucleation of CaOx or by the transformation of the outer layer of CaP crystals into CaOx crystals. Should this theory hold true, developing an understanding of the cellular mechanisms involved in progression of a small, basic interstitial plaque to that of an expanding, penetrating plaque could assist in the development of new therapies for stone prevention.

KW - Calcification

KW - Calcium oxalate

KW - Hydroxyapatite

KW - Kidney stones

KW - Randall’s plaque

KW - Randall’s plug

UR - http://www.scopus.com/inward/record.url?scp=84922076821&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922076821&partnerID=8YFLogxK

U2 - 10.1007/s00240-014-0705-9

DO - 10.1007/s00240-014-0705-9

M3 - Article

C2 - 25119506

AN - SCOPUS:84922076821

VL - 43

SP - 109

EP - 123

JO - Urolithiasis

JF - Urolithiasis

SN - 2194-7228

IS - 1

ER -