Pathogenesis of Calcium Oxalate Kidney Stones, Interactions Among Mitochondria, NADPH Oxidase and Endoplasmic Reticulum

Calcium oxalate (CaOx) nephrolithiasis is a common urological disease affecting people of all genders, age and races. Patients are generally treated surgically, prescribed medicine and advised to keep hydrated in addition to making dietary modifications. Despite advances, the stone recurrence rate has remained constant, between 30 to 50%. In addition, stones can lead to other renal diseases and even chronic kidney disease (CKD). Thus, a clearer understanding of the pathogenesis is paramount to devising improved treatment options. CaOx stones are the result of many factors including hyperoxaluria and CaOx crystals, both of which have been shown to cause the production of reactive oxygen species (ROS), development of oxidative stress (OS), and localized inflammation and fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mitochondria and endoplasmic reticulum (ER) all play significant roles in ROS production. They have been extensively investigated, mostly on an individual basis, for their possible involvement in crystal-induced renal cellular injuries. ROS-induced ROS release (RIRR) is a concept of small bursts of ROS triggering further ROS formation in other organelles. We have reviewed the available data of ROS production by NADPH oxidase, ER and mitochondria and examined the implications of possible interactions among them. We propose that CaOx crystals activate the epithelial renin-angiotensin aldosterone system (RAAS) and NADPH oxidase, leading to the production of ROS, which causes mitochondrial dysfunction and ER stress. RIRR leads to sustained OS, stimulating inflammasomes and the release of proinflammatory interleukins, resulting in cell death and fibrosis. Osteogenic signaling pathways are initiated promoting the deposition of calcium phosphate (CaP), which can then result in the formation of Randall’s plaque, the nidus for idiopathic CaOx stones. Dead and dying cells promote the formation of crystal plugs, which can act as stone nidus at the papillary tips.