Calcium phosphate crystals and kidney damage in mice and people
What it found
In mice, calcium phosphate crystals that form in kidney tubules damaged tubule cells and led to kidney scarring and nephron loss.
In people with diabetes and high cholesterol, higher blood levels of the hormone FGF23 were linked to more kidney events over 5 years.
What they found
Studies in people
FGF23 and kidney events in people
In 5039 people with diabetic eye disease and high cholesterol, those with FGF23 above 53 pg/mL had more kidney events over 5 years (3.2% vs 0.6%). The link remained after adjusting for age, sex, BMI, and serum creatinine.
Animal and lab studies
Crystal formation in tubules
In mice on a high-phosphate diet, microscopic particles containing calcium phosphate crystals appeared in the kidney tubule fluid. These particles were not seen in mice on a regular diet.
Crystals damage tubule cells
In lab tests, calcium phosphate particles, but not phosphate alone, killed human kidney tubule cells. Removing the particles or blocking their formation prevented cell death.
TLR4 receptor needed
Mice without the TLR4 gene in kidney tubules had less tubule damage, inflammation, and scarring from a high-phosphate diet, even though they excreted the same amount of phosphate in urine.
FGF23 threshold in mice
In mice, blood levels of the hormone FGF23 started to rise when the estimated phosphate concentration in the proximal tubule fluid went above 5.18 mg/dL. Higher FGF23 was followed by markers of tubule damage, inflammation, and scarring.
Nephron loss in mice
Mice with a prolonged increase in phosphate excretion per nephron (above 1.1 μg/d) lost nephrons over 12 weeks. A higher level (above 3.4 μg/d) was needed to reduce kidney function within that time.
What the authors conclude
“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.”
Also in their conclusions
- They propose that phosphate restriction aimed at lowering serum FGF23 below 53 pg/mL may benefit people with reduced nephron numbers, such as the elderly and patients with early-stage CKD.
- They suggest that agents like bisphosphonates that inhibit the formation of calcium phosphate crystals may be useful for this patient group.
- They call for randomized controlled trials to test whether reducing phosphate intake or absorption can slow nephron loss.
How it was done
The Western diet is rich in phosphate, but the potential harms of too much phosphate are poorly recognized. The authors wanted to find out how dietary phosphate damages the kidney and to identify a target for preventing kidney disease progression.
They studied mice fed high-phosphate diets for up to 12 weeks, some with reduced kidney function from surgery, and measured kidney damage, FGF23 levels, and nephron numbers. They also measured FGF23 and estimated phosphate concentration in kidney tubules in 148 people with kidney disease and followed 5039 people with diabetic eye disease and high cholesterol for 5 years.
What it can’t tell you
- The human part of this study followed people over time and found a link between higher FGF23 and kidney events, but it cannot prove that FGF23 causes the events.
- The mouse experiments show what happened in mice, not in people.
- The authors note that the causality of the FGF23 link remains to be determined by randomized controlled trials.
Who paid
- Funding
- Funded by NIA NIH HHS; NIDDK NIH HHS (from the PubMed record).
- Conflicts
- Conflict of interest: The authors have declared that no conflict of interest exists.
- Authors work at
- Jichi Medical University, Japan; University of Tokyo, Japan; Department of Clinical Laboratory Medicine, and
The paper
- Title
- Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression
- Type
- Study
- Evidence
- Studies in people · animals · lab
- Summarised from
- Full text
- Cite
- Shiizaki K, Tsubouchi A, Miura Y, et al (2021). Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression. The Journal of clinical investigation. doi:10.1172/JCI145693Free full textPubMed 34185705DOI
Summary written 26 Sep 2026. Check it against the paper before it changes what you eat. How we summarise papers · Report an error