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

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. Calcium oxalate kidney stones are often found attached to Randall’s plaques in the kidney papilla. Here, the authors examine the mechanisms underlying the formation of Randall’s plaques, including the role of mineralization modulators, as well as inflammation and immune cells. 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 c