Pyrophosphate homeostasis during calcifying diseases ; Homéostasie du pyrophosphate dans les maladies calcifiantes

Some chronic diseases, notably liver or kidney diseases, are associated with a high prevalence of arterial calcification, the determinants of which are not known. In the most advanced stages of these diseases, characterized by organ fibrosis and then organ failure, liver or kidney transplantation is suggested.Pyrophosphate is a potent circulating physiological inhibitor of calcification. In pathology, pyrophosphate deficiency is associated with arterial calcifications during genetic diseases due to mutations in the genes coding for ABCC6 (adenosine triphosphate ATP-binding cassette, subfamily C, member 6) or ENPP-1 (ectonucleotide pyrophosphatase/phosphodiesterase 1). Both proteins are mainly expressed in the liver and are involved in pyrophosphate synthesis while it is eliminated by urinary and alkaline phosphatase hydrolysis. The influence of organ transplantation on pyrophosphate homeostasis is unknown.The objectives of this thesis are to study the determinants of plasma pyrophosphate concentration and arterial calcifications before and after liver or kidney transplantation.In the first part, a new standardized method for determining the concentration of inorganic pyrophosphate in different biological fluids (culture media, plasma, urine, saliva, joint fluid) was developed. A European patent application has been filed.In the second part, haemodialysis and kidney transplant patients were compared to each other and to controls. Both haemodialysis and transplant patients have a pyrophosphate deficit compared to controls. Urinary pyrophosphate excretion is unchanged. Plasma ENPP1 activity is identical between groups but plasma alkaline phosphatase activity is negatively correlated with plasma pyrophosphate concentration. Pyrophosphate deficiency persists in renal transplant patients despite normal plasma alkaline phosphatase activity two years after transplantation.In the third part, patients with hepatic fibrosis and hepatocellular insufficiency, of varying etiologies, were compared before and 3 months after ...