A growth factor receptor turns up in calcifying uraemic arteries

Design

ex vivo murine aortic calcification model with uraemic dialysate, inducible VSMC-specific transgenic mice, and comparison of human arterial tissue

Population

murine aortas and CKD animal models; arteries from patients with CKD stage 5 versus age- and sex-matched controls without CKD

Primary outcome

vascular calcification and PDGFR-β phosphorylation

Effect

uraemic conditions raised PDGFR-β phosphorylation and calcification; inhibition with soluble PDGFR-β or imatinib reduced calcification and improved vascular elasticity; constitutively active PDGFR-β increased calcification

Vascular calcification in chronic kidney disease has resisted treatment for decades, partly because the target has been the mineral chemistry rather than the cells doing the calcifying. This work implicates platelet-derived growth factor receptor β in the phenotypic switch that turns vascular smooth muscle cells osteogenic.

Murine aortas incubated with dialysis fluid from patients on haemodialysis showed increased receptor phosphorylation and calcification, as did aortas from animals with chronic kidney disease. Blocking the signalling — with soluble receptor or with imatinib — reduced calcification and improved vascular elasticity. Transgenic mice expressing a constitutively active form of the receptor in smooth muscle cells calcified more, and more still under uraemic conditions. In human tissue, arteries from patients with stage 5 chronic kidney disease showed the same receptor activation and phenotypic switch against age- and sex-matched controls without kidney disease.

This is research-stage and belongs in that category — nothing here is a reason to prescribe anything. It is worth knowing for two reasons. Imatinib is an existing drug with a known safety profile, which shortens the distance to a trial. And the human tissue arm means the mechanism is not purely a mouse phenomenon, which is where most calcification targets have failed.

• This is preclinical with a supporting human tissue arm; do not use imatinib for vascular calcification
• Continue the established measures: phosphate control, avoiding calcium loading, managing parathyroid hormone
• The finding is about the vascular smooth muscle cell phenotype, not about mineral concentrations
• Repurposing an existing tyrosine kinase inhibitor is the plausible route to a trial
• Watch for a phase 1 or 2 study before this changes anything

Why it matters

Calcification research has lacked a cell-level target with human tissue support, and this supplies one.

Don't overread it

Mouse models, ex vivo aortas and a human tissue comparison — this is mechanism, not evidence that inhibiting the receptor helps patients.

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