pyrophosphate and Hyperphosphatemia

We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.. Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

Topics: Abnormalities, Multiple; Aortic Diseases; Basal Ganglia Diseases; Calcinosis; Cartilage Diseases; Dental Enamel Hypoplasia; Diphosphates; Enzyme Replacement Therapy; Gaucher Disease; Hand Deformities, Congenital; Humans; Hyperostosis, Cortical, Congenital; Hyperphosphatemia; Interferons; Metacarpus; Muscular Diseases; Odontodysplasia; Osteoporosis; Phosphates; Progeria; Pseudoxanthoma Elasticum; Pulmonary Valve Stenosis; Vascular Calcification

With documented high specificity, 99m Tc-pyrophosphate (PYP) scan enables the diagnosis of transthyretin cardiomyopathy to be made reliably without endomyocardial biopsy in patients who do not have monoclonal gammopathy. We report a case with extensive myocardial uptake of Perugini 3 score in the 3-hour 99m Tc-PYP myocardial SPECT that suggested transthyretin cardiac amyloidosis. However, a followed endomyocardial biopsy revealed no amyloid deposition. In this case, hyperphosphatemia was the most likely and presumptive cause of the false-positive 99m Tc-PYP scan. With this case, our experiences of the potential causes of false-positive results of 99m Tc-PYP are further expanded.

Topics: Biopsy; Cardiomyopathies; Diphosphates; Humans; Hyperphosphatemia; Prealbumin; Technetium; Technetium Tc 99m Pyrophosphate

A 63-year-old woman presented with intestinal disorder, alternating between obstipation and diarrhoea. Sodium phosphate/diphosphate (Fleet®) was used in preparation for colonoscopy. Within 24 h the patient developed severe hyperphosphatemia and oliguric acute kidney failure with the need of renal replacement therapy. This case illustrates the rare event of phosphate nephropathy after colonoscopy.

Topics: Acute Kidney Injury; Colonoscopy; Diphosphates; Female; Humans; Hyperphosphatemia; Laxatives; Middle Aged; Premedication; Renal Replacement Therapy; Treatment Outcome

Vascular calcification is a multifaceted process involving gain of calcification inducers and loss of calcification inhibitors. One such inhibitor is inorganic pyrophosphate (PP(i)), and regulated generation and homeostasis of extracellular PP(i) is a critical determinant of soft-tissue mineralization. We recently described an autocrine mechanism of extracellular PP(i) generation in cultured rat aortic vascular smooth muscle cells (VSMC) that involves both ATP release coupled to the ectophosphodiesterase/pyrophosphatase ENPP1 and efflux of intracellular PP(i) mediated or regulated by the plasma membrane protein ANK. We now report that increased cAMP signaling and elevated extracellular inorganic phosphate (P(i)) act synergistically to induce calcification of these VSMC that is correlated with progressive reduction in ability to accumulate extracellular PP(i). Attenuated PP(i) accumulation was mediated in part by cAMP-dependent decrease in ANK expression coordinated with cAMP-dependent increase in expression of TNAP, the tissue nonselective alkaline phosphatase that degrades PP(i). Stimulation of cAMP signaling did not alter ATP release or ENPP1 expression, and the cAMP-induced changes in ANK and TNAP expression were not sufficient to induce calcification. Elevated extracellular P(i) alone elicited only minor calcification and no significant changes in ANK, TNAP, or ENPP1. In contrast, combined with a cAMP stimulus, elevated P(i) induced decreases in the ATP release pathway(s) that supports ENPP1 activity; this resulted in markedly reduced rates of PP(i) accumulation that facilitated robust calcification. Calcified VSMC were characterized by maintained expression of multiple SMC differentiation marker proteins including smooth muscle (SM) alpha-actin, SM22alpha, and calponin. Notably, addition of exogenous ATP (or PP(i) per se) rescued cAMP + phosphate-treated VSMC cultures from progression to the calcified state. These observations support a model in which extracellular PP(i) generation mediated by both ANK- and ATP release-dependent mechanisms serves as a critical regulator of VSMC calcification.

Topics: Adenosine Triphosphate; Alkaline Phosphatase; Animals; Autocrine Communication; Calcinosis; Calcium-Binding Proteins; Calponins; Cells, Cultured; Cyclic AMP; Diphosphates; Homeostasis; Hyperphosphatemia; Kinetics; Male; Membrane Proteins; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphate Transport Proteins; Phosphoric Diester Hydrolases; Pyrophosphatases; Rats; Rats, Sprague-Dawley; RNA, Messenger