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 2/2 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 2/2 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 2/2 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 2/2 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.
Conflict of interest: EL and MD have filed a patent related to the use of stiripentol as a treatment against nephrolithiasis and ethylene glycol poisoning (WO2017140658 A1).
Most of kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla is considered to be at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analysed whether long-term exposure of Abcc6-/mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6-/and wild-type) received vitamin D alone (100,000 UI/Kg every 2 weeks), a calcium-enriched diet alone (calcium gluconate 2g/l in drinking water), both vitamin D supplementation and calcium rich diet, or a standard diet (controls) for 6 months. Kidney calcifications were assessed by 3Dmicro-computed tomography, µ-Fourier transform infrared spectroscopy, field emissionscanning electron microscopy, transmission electron microscopy and Yasue staining. At 6 months, Abcc6-/mice exposed to vitamin D and calcium supplementation developed massive Randall's plaque when compared to control Abcc6-/mice (p<0.01). Wild-type animals did not develop significant calcifications when exposed to vitamin D. Combined administration of vitamin D and calcium accelerates significantly Randall's plaque formation in a murine model. This original model raises concerns about the cumulative risk of vitamin D supplementation and calcium intakes in Randall's plaque formation.
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