Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

Abstract

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.

Keywords: Randall’s plaque; kidney; pseudoxanthoma elasticum; pyrophosphate.

Figure 1

Systemic Pyrophosphate (PPi) synthesis. ABCC6 (expressed in hepatocytes and proximal tubular cells) and NPP1 (in arteries and capillaries) combined activity generates AMP in addition to PPi. AMP is rapidly converted into adenosine by CD73, which exerts a tonic inhibition on tissue non-specific alkaline enzyme (TNAP). TNAP degrades PPi to generate inorganic phosphate and promotes hydroxyapatite precipitation in ectopic tissues. ANK allows PPi externalization from cells, its role in ectopic calcifications is unclear.