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Chronic kidney disease (CKD) has reached epidemic proportions globally. The natural course of chronic kidney disease is almost uniformly progressive, albeit at different rates in different individuals. The downhill course appears to pervade kidney diseases of all etiologies and seems to spiral down a self-perpetuating vortex, even if the original insult is ameliorated or controlled. In this issue of the JCI, Shiizaki, Tsubouchi, and colleagues proposed a model of renal tubule luminal calcium phosphate crystallopathy that accounts for renal function demise. Calcium phosphate crystals attached to TLR4 and underwent endocytosis at the brush border, triggering inflammation and fibrosis. This mechanism might operate in different kinds of kidney disease, with a theoretical phosphate concentration threshold in the proximal tubular lumen, beyond which is triggered undesirable downstream effects that eventuate in loss of renal function. If this model parallels human CKD, clinicians may focus efforts on determining phosphate exposure in the proximal tubular lumen., Chronic kidney disease progression is universal Chronic kidney disease (CKD) has reached epidemic proportions globally, imparting dire health and economic burdens on humankind. The progression of CKD appears to be [...]