Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease

Abstract

IntroductionPatients on dialysis and kidney transplant recipients (KTR) present the syndrome of mineral and bone disorders (MBD), which share common traits with monogenic calcifying diseases related to disturbances of the purinergic system. Low plasma levels of inorganic pyrophosphate (PPi) and ectopic vascular calcifications belong to these two conditions. This suggests that the purinergic system may be altered in chronic kidney disease with MBD. Therefore, we perform a transversal pilot study in order to compare the determinants of PPi homeostasis and the plasma levels of PPi in patients on dialysis, in KTR and in healthy people.Patients and MethodsWe included 10 controls, 10 patients on maintenance dialysis, 10 early KTR 3 ± 1 months after transplantation and nine late KTR 24 ± 3 months after transplantation. We measured aortic calcifications, plasma and urine levels of PPi, the renal fractional excretion of PPi (FePPi), nucleoside triphosphate hydrolase (NPP) and ALP activities in plasma. Correlations and comparisons were assessed with non-parametric tests.ResultsLow PPi was found in patients on dialysis [1.11 (0.88–1.35), p = 0.004], in early KTR [0.91 (0.66–0.98), p = 0.0003] and in late KTR [1.16 (1.07–1.45), p = 0.02] compared to controls [1.66 (1.31–1.72) μmol/L]. Arterial calcifications were higher in patients on dialysis than in controls [9 (1–75) vs. 399 (25–526) calcium score/cm2, p < 0.05]. ALP activity was augmented in patients on dialysis [113 (74–160), p = 0.01] and in early KTR [120 (84–142), p = 0.002] compared to controls [64 (56–70) UI/L]. The activity of NPP and FePPi were not different between groups. ALP activity was negatively correlated with PPi (r = −0.49, p = 0.001).DiscussionPatients on dialysis and KTR have low plasma levels of PPi, which are partly related to high ALP activity, but neither to low NPP activity, nor to increased renal excretion of PPi. Further work is necessary to explore comprehensively the purinergic system in chronic kidney disease.

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation

“…We measured higher plasma ALP activity in LT candidates than in LT recipients (190 [87-321] vs. 81 [65-158] UI/L, p = 0.05) (Table 1). Plasma ALP activity negatively correlated with [PPi]pl at baseline (r = −0.54, p = 0.0003), as expected [17]. The two diagrams are a representation of the relation between the PPi homeostasis in hepatocytes and arterial calcification.…”

“…The secondary outcomes were the assessments of: We hypothesized that [PPi]pl were low in LT candidates and were restored within the normal range three months after LT. We estimated, based on a previous study [17], that the participation of ten patients would sufficiently power the study to identify a significant difference in the median [PPi]pl before and after LT.…”

Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum

“…In patients affected by CKD, high serum phosphate levels increase the calcium-phosphate supersaturation and are associated with vascular calcification and cardiovascular mortality. Interestingly, a deficiency in pyrophosphate has also been described in CKD patients and may play an important role in the development of cardiovascular calcification [8,18]. Calcium phosphate supersaturation is probably necessary for the development of vascular calcification but phosphate, and to a lesser extent calcium, may also exert an active function on vascular smooth muscle cells by changing their phenotype into osteoblast-like cells expressing RUNX2 and other osteogenic genes, increasing mineralization in arterial media [19].…”

The Role of Purinergic Signaling in Heart Transplantation

“…Currently, four APs have been identified, and they are named according to their tissue distribution characteristics: placental AP (PLAP), germ-cell AP, intestinal AP (IAP), and the tissue-nonspecific form of AP (TNAP). TNAP is mainly involved in bone mineralization, and disturbance of phosphate metabolism in chronic kidney disease ( 28 , 29 ). In addition, AK is the critical enzyme responsible for cellular adenine nucleotide homeostasis through the catalysis of the reaction 2ADP ↔ ATP + AMP.…”