ABCC6 Deficiency Promotes Development of Randall Plaque.

Abstract

BACKGROUND:

Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the ABCC6 gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models.

METHODS:

We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from Abcc6-/- mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications.

RESULTS:

Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). Abcc6-/- mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, Abcc6-/- mice had low urinary excretion of pyrophosphate.

CONCLUSIONS:

The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and Abcc6-/- mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.

• Authors: Emmanuel Letavernier, Gilles Kauffenstein, Léa Huguet, Nastassia Navasiolava, Elise Bouderlique, Ellie Tang, Léa Delaitre, Dominique Bazin, Marta de Frutos, Clément Gay, Joëlle Perez, Marie-Christine Verpont, Jean-Philippe Haymann, Viola Pomozi, Janna Zoll, Olivier Le Saux, Michel Daudon, Georges Leftheriotis, Ludovic Martin
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 9 Pg. 2337-2347 (09 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 29991491 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• ABCC6 protein, human
• ATP-Binding Cassette Transporters
• Abcc6 protein, mouse
• Multidrug Resistance-Associated Proteins

Topics

• ATP-Binding Cassette Transporters (genetics)
• Animals
• Biopsy, Needle
• Calcinosis (genetics, pathology)
• Cohort Studies
• Disease Models, Animal
• Female
• Humans
• Immunohistochemistry
• Incidence
• Kidney Calculi (epidemiology, etiology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Multidrug Resistance-Associated Proteins (genetics)
• Prognosis
• Pseudoxanthoma Elasticum (complications, diagnostic imaging, genetics, pathology)
• Retrospective Studies
• Risk Assessment
• Tomography, X-Ray Computed (methods)
• Urinalysis