pyrophosphate and Renal-Insufficiency--Chronic

Pathologic cardiovascular calcification is associated with a number of conditions and is a common complication of chronic kidney disease. Because ambient calcium and phosphate levels together with properties of the vascular matrix favor calcification even under normal conditions, endogenous inhibitors such as pyrophosphate play a key role in prevention. Genetic diseases and animal models have elucidated the metabolism of extracellular pyrophosphate and demonstrated the importance of pyrophosphate deficiency in vascular calcification. Therapies based on pyrophosphate metabolism have been effective in animal models, including renal failure, and hold promise as future therapies to prevent vascular calcification.

Topics: Animals; Blood Vessels; Calcium; Diphosphates; Down-Regulation; Genetic Predisposition to Disease; Humans; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification

The objective of this short review is to evaluate the efficacy of ferric pyrophosphate citrate and to determine its place in therapy based on the current published literature.. A literature search was conducted and pared down to yield 4 placebo controlled Phase II and III clinically relevant trials.. Ferric pyrophosphate citrate is a new intradialytic iron supplementation product that has been found to reduce the dose of erythropoiesis-stimulating agents and intravenous iron supplementation and to increase serum ferritin concentrations.. This agent may be administered to patients with stage 5 chronic kidney disease receiving hemodialysis as a new iron supplementation option to maintain hemoglobin, transferrin saturation, and ferritin concentrations.

Topics: Administration, Intravenous; Citrates; Dietary Supplements; Diphosphates; Ferritins; Hematinics; Hemoglobins; Humans; Iron; Renal Dialysis; Renal Insufficiency, Chronic

The cardiovascular risk of patients undergoing dialysis is 20-30 times higher than that of individuals of the same age, without abnormal renal function, from the general population. Observational studies of patients with normal and abnormal renal function have shown that there is an association between bone disease, vascular calcification and cardiovascular outcome and that worsening of these conditions happens in parallel. Basic science studies are elucidating several mechanisms that could explain the interaction between bone disease, vascular calcification and cardiovascular outcome. For example, the expression of osteoprotegerin-a protein that regulates bone resorption by binding receptor activator of nuclear factor kappaB (RANK) ligand (RANKL), thus preventing interaction with the receptor RANK and the stimulation of osteoclast maturation-is regulated by several cytokines. Additionally, osteoprotegerin seems involved in the genesis of atherosclerosis. Imbalances of bone mineral metabolism, bone matrix secretion and vascular smooth-muscle-cell apoptosis seem involved in the ossification of the arterial wall in chronic kidney disease, and could explain some of the complex interactions between bone and vascular disease in renal failure. In this article we present a brief review of some of the basic mechanisms involved in vascular calcification and the clinical evidence of an association of vascular and bone disease.

Topics: Aged; alpha-2-HS-Glycoprotein; Blood Proteins; Bone and Bones; Bone Diseases; Calcinosis; Calcium; Calcium-Binding Proteins; Diphosphates; Extracellular Matrix Proteins; Female; Humans; Male; Matrix Gla Protein; Middle Aged; Osteoporosis; Phosphates; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Vascular Diseases

Iron deficiency is a common cause of anemia in pediatric patients with hemodialysis-dependent chronic kidney disease (CKD-5HD). Ferric pyrophosphate citrate (FPC, Triferic®) donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Administration of FPC via dialysate or intravenously (IV) may provide a suitable therapeutic option to current IV iron preparations for these patients.. The pharmacokinetics and safety of FPC administered via dialysate and IV to patients aged < 6 years (n = 3), 6 to < 12 years (n = 4), and 12 to <18 years (n = 15) were investigated in a multicenter, open-label, two-period, single-dose study. FPC (0.07 mg iron/kg) was infused IV into the venous blood return line during hemodialysis session no. 1. FPC iron was added to bicarbonate concentrate to deliver 2 μM (110 μg/L) iron via dialysate during hemodialysis session no. 2.. Mean serum total iron concentrations peaked 3 to 4 h after administration via dialysate and 2 to 4 h after IV administration and returned to baseline by 10 h after the start of hemodialysis for both routes. Iron exposure was greater after administration via dialysate than after IV administration. The absolute amount of absorbed iron after administration via dialysate roughly doubled with increasing age, but the weight-normalized amount of absorbed iron was relatively constant across age groups (~ 0.06-0.10 mg/kg). FPC was well tolerated in the small number of patients studied.. FPC iron can be administered to pediatric patients with CKD-5HD via dialysate or by the IV route. Further study of FPC administered to maintain hemoglobin concentration is indicated.

Topics: Administration, Intravenous; Adolescent; Anemia, Iron-Deficiency; Child; Child, Preschool; Dialysis Solutions; Diphosphates; Feasibility Studies; Female; Hematinics; Hemoglobins; Humans; Infant; Iron; Male; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Anemia is a common complication in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Anemia is principally the result of erythropoietin deficiency, inflammation, and iron deficiency. High molecular weight iron oxide nanoparticles (IONP) are routinely administered intravenously to replace iron losses and, although effective, there are lingering concerns about possible safety issues. Ferric pyrophosphate citrate (FPC, Triferic, Triferic AVNU [Triferic and Triferic AVNU are the proprietary name for ferric pyrophosphate citrate. Triferic and Triferic AVNU are registered trademarks of Rockwell medical Inc.]) is a complex iron salt that donates iron directly to plasma transferrin. FPC is devoid of any carbohydrate moiety and is administered

Topics: Anemia; Anemia, Iron-Deficiency; Citrates; Dialysis Solutions; Diphosphates; Ferric Compounds; Hemoglobins; Humans; Inflammation; Iron; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone fetuin-A deficient mice were alternatively treated with parenteral administration of fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum fetuin-A, magnesium and pyrophosphate levels.

Topics: alpha-2-HS-Glycoprotein; alpha-Fetoproteins; Animals; Calcinosis; Diphosphates; Disease Models, Animal; Female; Kidney; Liver; Magnesium; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microvessels; Minerals; Multidrug Resistance-Associated Proteins; Renal Insufficiency, Chronic; TRPM Cation Channels

Topics: Anemia, Iron-Deficiency; Citrates; Diphosphates; Ferric Compounds; Hematinics; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Vascular calcification significantly contributes to mortality in chronic kidney disease (CKD) patients. Sevelamer and pyrophosphate (PPi) have proven to be effective in preventing vascular calcification, the former by controlling intestinal phosphate absorption, the latter by directly interfering with the hydroxyapatite crystal formation. Since most patients present with established vascular calcification, it is important to evaluate whether these compounds may also halt or reverse the progression of preexisting vascular calcification. CKD and vascular calcification were induced in male Wistar rats by a 0.75 % adenine low protein diet for 4 weeks. Treatment with PPi (30 or 120 µmol/kg/day), sevelamer carbonate (1500 mg/kg/day) or vehicle was started at the time point at which vascular calcification was present and continued for 3 weeks. Hyperphosphatemia and vascular calcification developed prior to treatment. A significant progression of aortic calcification in vehicle-treated rats with CKD was observed over the final 3-week period. Sevelamer treatment significantly reduced further progression of aortic calcification as compared to the vehicle control. No such an effect was seen for either PPi dose. Sevelamer but not PPi treatment resulted in an increase in both osteoblast and osteoid perimeter. Our study shows that sevelamer was able to reduce the progression of moderate to severe preexisting aortic calcification in a CKD rat model. Higher doses of PPi may be required to induce a similar reduction of severe established arterial calcification in this CKD model.

Topics: Animals; Aorta; Chelating Agents; Diphosphates; Durapatite; Male; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Sevelamer; Vascular Calcification

Chronic kidney disease (CKD) is generally associated with disturbances of mineral and bone metabolism. They contribute to the development of vascular calcification (VC), a strong, independent predictor of cardiovascular risk. Pyrophosphate (PPi), an endogenous inhibitor of hydroxyapatite formation, has been shown to slow the progression of VC in uremic animals. Since in patients with CKD treatment is usually initiated for already existing calcifications, we aimed to compare the efficacy of PPi therapy with that of the phosphate binder sevelamer, using a uremic apolipoprotein-E knockout mouse model with advanced VCs. After CKD creation or sham surgery, 12-week-old female mice were randomized to one sham group and four CKD groups (n = 18-19/group). Treatment was initiated 8 weeks after left nephrectomy allowing prior VC development. Uremic groups received either intraperitoneal PPi (high dose, 1.65 mg/kg or low dose, 0.33 mg/kg per day), oral sevelamer (3 % in diet), or placebo treatment for 8 weeks. Both intima and media calcifications worsened with time in placebo-treated CKD mice, based on both quantitative image analysis and biochemical measurements. Progression of calcification between 8 and 16 weeks was entirely halted by PPi treatment, as it was by sevelamer treatment. PPi did not induce consistent bone histomorphometry changes. Finally, the beneficial vascular action of PPi probably involved mechanisms different from that of sevelamer. Further studies are needed to gain more precise insight into underlying mechanisms and to see whether PPi administration may also be useful in patients with CKD and VC.

Topics: Animals; Apolipoproteins E; Diphosphates; Disease Models, Animal; Disease Progression; Infusions, Parenteral; Mice; Mice, Knockout; Renal Insufficiency, Chronic; Uremia; Vascular Calcification

Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T50) of calciprotein particles in serum was described. We used this test to measure serum T50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T50 tertile was more than two times the risk among patients in the highest T50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

Topics: Aged; Aged, 80 and over; alpha-2-HS-Glycoprotein; Arteriosclerosis; Biomarkers; Calcinosis; Calcium Phosphates; Cardiovascular Diseases; Causality; Comorbidity; Diabetes Mellitus; Diphosphates; Disease Susceptibility; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Mortality; Osteoclasts; Phosphates; Prospective Studies; Pulse Wave Analysis; Renal Dialysis; Renal Insufficiency, Chronic; Risk; Serum Albumin; Smoking; Vascular Resistance

Vascular calcification (VC) is a risk factor for cardiovascular mortality in the setting of chronic kidney disease (CKD). Pyrophosphate (PPi), an endogenous molecule that inhibits hydroxyapatite crystal formation, has been shown to prevent the development of VC in animal models of CKD. However, the possibility of harmful effects of exogenous administration of PPi on bone requires further investigation. To this end, we examined by histomorphometry the bone of CKD mice after intraperitoneal PPi administration. After CKD creation or sham surgery, 10-week-old female apolipoprotein-E knockout (apoE(-/-)) mice were randomized to one non-CKD group or 4 CKD groups (n = 10-35/group) treated with placebo or three distinct doses of PPi, and fed with standard diet. Eight weeks later, the animals were killed. Serum and femurs were sampled. Femurs were processed for bone histomorphometry. Placebo-treated CKD mice had significantly higher values of osteoid volume, osteoid surface and bone formation rate than sham-placebo mice with normal renal function. Slightly higher osteoid values were observed in CKD mice in response to very low PPi dose (OV/BV, O.Th and ObS/BS) and, for one parameter measured, to high PPi dose (O.Th), compared to placebo-treated CKD mice. Treatment with PPi did not modify any other structural parameters. Mineral apposition rates, and other parameters of bone formation and resorption were not significantly different among the treated animal groups or control CKD placebo group. In conclusion, PPi does not appear to be deleterious to bone tissue in apoE(-/-) mice with CKD, although a possible stimulatory PPi effect on osteoid formation may be worth further investigation.

Topics: Animals; Apolipoproteins E; Bone Density; Dialysis Solutions; Diphosphates; Female; Femur; Mice; Mice, Knockout; Peritoneal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification