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, hypocitraturia), renal stress or trauma, and perhaps even the normal aging process leads to transformation of renal epithelial cells into an osteblastic 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 subepithelial 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.

Osteogenic changes in kidneys of hyperoxaluric rats

“…[10, 14, 61] Pathogenesis of the plaques, where and how do they begin and grow, is however not well understood. The observations that stone formation and cardiovascular diseases such as hypertension, myocardial infarction, carotid artery atherosclerosis, coronary heart disease,[4, 5, 62, 63] often co-exist and share risk factors, markers and outcomes have led us to hypothesize that similar molecules and pathways may be involved in vascular calcification and RP formation.…”

“…But it alone cannot explain the formation of Randall’s plaques, which are common even in non-stone formers. [10, 12] There is the possibility of other instigators and situations, such as reduction in crystallization inhibitory capacity as shown in THP null mice. [66] Lack of overt inflammation around the plaques would also indicate malfunctioning crystal clearance system.…”

“…[10–14] The plaques themselves originate deep inside the renal interstitium associated with the basement membranes of loops of Henle, collecting ducts or blood vessels. [15, 16] Mechanisms involved in the initial formation of the RPs are still unclear.…”

Timelines of the “free-particle” and “fixed-particle” models of stone-formation: theoretical and experimental investigations

“…Again compounds like osteopontin are found in plaques [27] but there are no signs of active removal. Through a sequence of alternating accumulations of crystal components and organic material these deposits increase in size following a layered growth pattern.…”

Mechanism of Randall’s Plugs Development

“…These calcifications can be classified as two clearly different entities [1]. One type results from a subepithelial calcification (hydroxyapatite) of the renal papilla following pre-existing injury.…”