Journal Article

Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression

Hayashi, Hirosaka, Miura, Marina, Battulga, Batpurev, Hara, Toru, Negishi, Keita, Ohno, Nobuhiko, Shiizaki, Kazuhiro, Tsubouchi, Asako, Kunishige, Rina, Nagata, Daisuke, Komuro, Issei, Kuchimaru, Takahiro, Kotani, Kazuhiko, Kuro-o, Makoto, Iwazu, Yoshitaka, Masutani, Mamiko, Itoh, Hiroshi, Miura, Yutaka, Kario, Kazuomi, Seo, Kinya, Yamada, Toshiyuki, Kurosu, Hiroshi, Murata, Masayuki

2021

Overview

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.

• Publisher: American Society for Clinical Investigation
• Subject: Acidification / Aging / Animals / Apoptosis / Biomedical research / Bisphosphonates / Body Fluids - chemistry / Calcium phosphate / Calcium phosphates / Calcium Phosphates - chemistry / Calcium Phosphates - metabolism / Calories / Cell Line / Chemical properties / Chronic kidney failure / Crystallization / Crystals / Development and progression / Diet / Diet, Western - adverse effects / Disease Progression / Endocytosis / Fibroblast Growth Factor-23 / Fibroblast Growth Factors - blood / Fibrosis / Health aspects / Homeostasis / Humans / Hypotheses / Inflammation / Kidney diseases / Kidney tubules / Kidney Tubules - metabolism / Kidney Tubules - pathology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular crystals / Nephrons / Phase transitions / Phosphate / Phosphates - administration & dosage / Phosphates - adverse effects / Physiological aspects / Reabsorption / Renal Insufficiency, Chronic - etiology / Renal Insufficiency, Chronic - metabolism / Renal Insufficiency, Chronic - pathology / Renal tubules / Therapeutic targets / TLR4 protein / Toll-Like Receptor 4 - deficiency / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Urine