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.

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.

Whitlockite structures in kidney stones indicate infectious origin: a scanning electron microscopy and Synchrotron Radiation investigation

Understanding the physico-chemistry related to cristalline pathologies constitutes a challenge in several medical specialities such as nephrology, dermatology or oncology. Regarding nephrology, the chemical diversity of concretions such as kidney stones calls for characterization techniques to determine the chemical composition of concretions. The starting point of this contribution is given by Fourier Transform InfraRed (FTIR) spectroscopy which is routinely used at the hospital to determine the chemical composition of kidney stones as well as ectopic calcifications present in kidney biopsy. For kidney stones, the quantity of sample is sufficient to perform a significant analysis through classical FTIR. For ectopic calcifications, µFTIR can be inefficient in the case of µcalcification in the tissue when their size is less than 10 µm. For such samples, Optical PhotoThermal IR (OPT-IR) spectroscopy may constitute a way to overcome this experimental difficulty through the acquisition of IR spectrum with a spatial resolution close to 500 nm.To illustrate such opportunity, we first compare the IR spectrum acquired with a classical experimental set-up related to classical IR spectroscopy to IR spectrum collected with a OPT-IR one for different compounds namely calcium oxalate monohydrate, calcium oxalate dehydrate, calcium phosphate apatite and magnesium ammonium phosphate hexahydrate. Such comparison helps us to assess specificity of OPT-IR. Then, we consider several pathological calcifications associated to hyperoxaluria, adenine phosphoribosyltransferase (APRT) deficiency or the presence of Randall's plaque. We will see that the nanometer spatial resolution constitutes a major advantage versus a micrometre one. Also, in the case of Randall's plaque, we show that OPT-IR can determine the chemical composition of microscopic concretion without any kind of preparation. Such experimental fact is clearly a major advantage. Finally, we also extended this first investigation in nephrology by considering breast calcifications. In that case, if the number of chemical phases is quite low compared to the number of chemical phases identified in ectopic calcifications present in kidney (four instead of 24), the challenge is related to the possibility to distinguish between the different calcium phosphate namely amorphous carbonated calcium phosphate, CA and whitlockite.The complete set of data indicates the limitations and the advantages of OPT-IR spectroscopy.

Despite the incidence of breast cancer among women, mammography and anatomopathology investigations are still the gold standard method for preventive screening and diagnosis. Several criteria are used to diagnose precisely the severity of the pathology like the distribution and shape of breast microcalcifications (BMCs). However, the link between the different chemical phases of BMCs and the cancer stage remains unclear. As BMCs physicochemical speciation has the potential to help clinicians during their diagnosis, this study aims to propose a methodology using advanced spectroscopical analysis techniques to finely characterize BMCs and uncover the relationship between

The majority of idiopathic calcium oxalate kidney stones form on the Randall's plaque, a subepithelial calcium phosphate plaque at the renal papilla. The formation mechanisms of the Randall's plaque and associated calcium oxalate stones remain incompletely understood. This article provides an historical overview of the research performed on this topic, describes the current epidemiological trends of Randall's plaque-associated kidney stone formation and reviews the suggested formation mechanisms of Randall's plaque and associated calcium oxalate stones. Finally, this overview highlights the recent advances made on the subject, including the development of an animal model.