Emmanuel Letavernier1,2,3, Gilles Kauffenstein4, Léa Huguet5,2, Nastassia Navasiolava6, Elise Bouderlique5,2, Ellie Tang5,2, Léa Delaitre6, Dominique Bazin7, Marta de Frutos7, Clément Gay7, Joëlle Perez5,2, Marie-Christine Verpont5,2, Jean-Philippe Haymann5,2,3, Viola Pomozi8, Janna Zoll8, Olivier Le Saux8, Michel Daudon5,2,3, Georges Leftheriotis9, Ludovic Martin4,6. 1. Unité Mixte de Recherche S 1155, Sorbonne Universités, Université Pierre et Marie Curie-Paris 06, Paris, France; emmanuel.letavernier@aphp.fr. 2. Unité Mixte de Recherche S 1155, Institut National de la Santé et de la Recherche Médicale, Paris, France. 3. Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France. 4. Institut des maladies mitochondriales, du coeur et des vaisseaux-MITOVASC, Centre National de la Recherche Scientifique 6015, Institut National de la Santé et de la Recherche Médicale U1083, Angers University, Angers, France. 5. Unité Mixte de Recherche S 1155, Sorbonne Universités, Université Pierre et Marie Curie-Paris 06, Paris, France. 6. Department of Dermatology, PseudoXanthoma Elasticum Consultation center, Reference Center for rare skin diseases, Angers University Hospital, France. 7. Unité Mixte de Recherche 8502, Laboratoire de Physique des Solides, Centre National de la Recherche Scientifique, Université Paris Sud XI, Orsay, France. 8. Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii; and. 9. Department of Physiology and Molecular Medicine, Unité Mixte de Recherche 7370, Centre National de la Recherche Scientifique, University of Nice, Nice, France.
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.
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.
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