Longitudinal Relationships among Coronary Artery Calcification, Serum Phosphorus, and Kidney Function

Tuttle, Katherine R.; Short, Robert

doi:10.2215/cjn.01250209

Cited by 94 publications

(80 citation statements)

References 27 publications

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“…31 Various studies have evidenced the downregulation of miR-125b, miR-221, miR-222, miRhealthy adults have demonstrated that phosphorus levels at the upper limit of the normal range are independently associated with a greater likelihood and a more rapid progression of coronary artery calcium. 14, 15 In a study involving 439 multi-ethnic participants with moderate CKD but no clinical signs of CVD, Adeney et al reported that each 1 mg/dl (0.32 mmol/L) increment in phosphate level is strongly (P=0.002) and independently associated with a higher prevalence of calcification. 13 Actual therapy to manage hyperphosphatemia in endstage CKD includes, among others, oral phosphate binders such as calcium acetate, sevelamer or lanthanum.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Gross

Six

Kamel

et al. 2014

Circ J

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In epidemiological studies of CKD patients and the general population, high phosphate levels are associated with CV disease (CVD). The association is even observed in early-stage CKD and is independent of other traditional CV risk factors. 5, 6 Along with other factors, hyperphosphatemia is involved in the development of vascular calcification (VC) and endothelial dysfunction (ED), 7-9 both of which are major nontraditional CV risk factors for CKD. Phosphate is able to act either directly on these parameters or indirectly via the FGF23/Klotho and PTH axes (Figure 1).We review the various effects of hyperphosphatemia on CV parameters, with a focus on its emerging role in ED. The efficacy of current therapies for improving phosphate-related CV outcomes is also discussed. Direct Effects of Phosphate on CV Calcification and ED Epidemiological and Interventional StudiesVC is deposition of calcium/phosphate, mostly as apatite, in the blood vessels, myocardium and cardiac valves. Calcification of both the intima and media occurs in CKD, 10 resulting in the stiffness of the large arteries (as evidenced by a higher pulse wave velocity) and thus promotion of CV morbidity/ mortality. The results of several epidemiological studies have highlighted an association between serum phosphate levels and VC in stage 5D CKD patients, 11,12 in early-stage CKD patients and in the general population (in whom serum phosphate levels are still within the normal range). 13, 14 Indeed, 2 elegant prospective studies of large cohorts of hosphate, principally provided by food, is involved in many physiological processes: it buffers the intracellular pH, ensures the stability of the skeleton and contributes to many essential biological functions (eg, DNA synthesis, cell membrane phospholipids, energy metabolism and intracellular signaling pathways that are regulated by phosphorylation/dephosphorylation).The physiological concentration of phosphate (0.8-1.5 mmol/L) is tightly regulated by, among others, the fibroblast growth factor 23 (FGF23)/Klotho axis, parathyroid hormone (PTH) and calcitriol (the active form of vitamin D). 1 In chronic kidney disease (CKD), the progressive loss of functional nephrons induces retention of phosphate, which in turn leads to (1) an increase in calcium/phosphate products and (2) FGF23 synthesis. With the aim of preventing hyperphosphatemia, FGF23 decreases circulating levels of calcitriol, thus inhibiting intestinal phosphate and calcium absorption. PTH, the overexpression of which is triggered by hypocalcemia, stimulates bone resorption for the primary purpose of restoring calcemia but in doing so it increases phosphatemia and thus the calcium/phosphate products. During the course of CKD, Klotho's downregulation in both the parathyroid gland and the kidney results in the loss of FGF23 being able to respectively (1) decrease PTH expression and (2) inhibit renal phosphate reabsorption. In late-stage CKD, the few remaining functional nephrons are no longer able to eliminate phosphate and a vicious circle (referred ...

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Section: In Vitro Studiesmentioning

confidence: 99%

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Gross

Six

Kamel

et al. 2014

Circ J

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“…73,91,142 Hyperphosphatemia is also a risk factor for cardiovascular disease and mortality in chronic kidney disease. 39,48,72,193 Excessive FGF23 results in left ventricular hypertrophy via a klotho-independent mechanism, likely via the calcineurin-NFAT pathway. 53,168 However, recent work has suggested that FGF23 also regulates the number of Na þ -Cl -cotransporters in the distal tubules of the kidney.…”

Section: 119mentioning

confidence: 99%

Fibroblast Growth Factor 23

Hardcastle¹,

Dittmer

2015

Vet Pathol

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Traditionally, control of phosphorus in the body has been considered secondary to the tighter control of calcium by parathyroid hormone and vitamin D. However, over the past decade, substantial advances have been made in understanding the control of phosphorus by the so-called phosphatonin system, the lynchpin of which is fibroblast growth factor 23 (FGF23). FGF23 binds to the klotho/FGFR1c receptor complex in renal tubular epithelial cells, leading to upregulation of Na/P i cotransporters and subsequent excretion of phosphorus from the body. In addition, FGF23 inhibits parathyroid hormone and the renal 1a-hydroxylase enzyme, while it stimulates 24-hydroxylase, leading to decreased 1,25-dihydroxyvitamin D 3 . FGF23 is intimately involved in the pathogenesis of a number of diseases, particularly the hereditary hypophosphatemic rickets group and chronic kidney disease, and is a target for the development of new treatments in human medicine. Little work has been done on FGF23 or the other phosphatonins in veterinary medicine, but increases in FGF23 are seen with chronic kidney disease in cats, and increased FGF23 expression has been found in soft tissue sarcomas in dogs.Keywords fibroblast growth factor 23, phosphatonin, phosphorus metabolism disorders, rickets, chronic renal failure, chronic kidney disease Fibroblast growth factor 23 (FGF23) is a recently recognized hormone that plays an intrinsic role in calcium and phosphorus metabolism, both in health and disease. Studies have shown that in humans, FGF23 is implicated in multiple inherited bone diseases, paraneoplastic bone disease (tumor-induced osteomalacia), and complications of chronic kidney disease and cardiovascular disease. In animals, a handful of studies have already recognized potential roles for FGF23 as a biomarker of disease and perhaps as a therapeutic agent. This review details the manner in which FGF23 joins established players in calciumphosphorus metabolism, current knowledge of its role in disease in humans and animals, and future avenues for research and use of this hormone.

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“…17 Em outra coorte, que incluiu pacientes com média de idade mais elevada (48 anos), seguidos por 6 anos, o Pi sérico na primeira avaliação foi preditor tanto do surgimento de calcificação coronariana quanto da sua progressão (razão de chance: 1,54, p=0,002), embora não tenha havido correlação entre os dois parâmetros basais. 18 Recentemente, estudo realizado na Universidade de São Paulo avaliou a associação entre vários marcadores e a presença de doença coronariana em 290 pacientes clinicamente estáveis, com suspeita de doença arterial coronariana e TFG estimada superior a 60 ml/min. 19 Esta avaliação foi realizada tanto através da quantificação da calcificação coronariana através de tomografia computadorizada quanto pela presença de lesões obstrutivas à cineangiocoronariografia.…”

Section: Fosfatounclassified

Papel Do Fosfato Na Doença Cardiovascular: Marcador Ou Causador De Lesão?

Almeida¹,

Cancela

Moises

et al. 2015

Rev. Med. UFPR

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RESUMOO fosfato (Pi) é um mineral essencial que participa de diversos processos metabólicos, como produção de energia e sinalização intracelular, além de ser um importante constituinte de diversos elementos celulares. A homeostase do Pi, estritamente regulada pelo paratormônio, pela vitamina D e pelo fator de crescimento fibroblástico -23, sofre um grande desequilíbrio com a perda da função renal, culminando com o desenvolvimento de hiperfosfatemia. Nessa revisão abordaremos a fisiologia do Pi e o seu desequilíbrio causado pela disfunção renal, que se revela através do desenvolvimento da sobrecarga de Pi e da própria hiperfosfatemia. Discutiremos ainda as principais evidências clínicas e experimentais que apontam para o Pi como o mais novo vilão das doenças cardiovasculares tanto na população renal crônica quanto na geral. As estratégias terapêuticas devem ser voltadas sobretudo para a redução da ingestão de Pi, que encontra-se aumentada nos dias atuais devido a presença de conservantes à base desse elemento utilizados nos alimentos industrializados. Estudos populacionais são urgentemente necessários para testar de modo mais amplo os possíveis efeitos benéficos do controle da sobrecarga de Pi sobre o sistema cardiovascular.Palavras chave: Fosfato; Doença Cardiovascular ABSTRACT Phosphate is an essential intracellular mineral that plays its role in a variety of metabolic pathways, like energy production and intracellular synthetis, apart from being and important block to various intracellular elements. Homeostasis of Pi, strictly regulated by parathormone, vitamin D and fibroblast growth factor 23, suffers greatly by the decline of renal function, as seen when phosphate overload and hyperphosphatemia takes its place. We will discuss the major clinical and experimental evidence that points to Pi as the newest villain of cardiovascular disease in the chronic renal disease population, as well as the population in general. Therapeutic strategies should be directed mainly in the reduction of Pi intake, that finds itself increased nowadays due to the presence of food preservatives based on this element in industrialized food. Populational studies are urgently needed to test in a more broad way the possible benefic effects of Pi overload control on cardiovascular system.

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Longitudinal Relationships among Coronary Artery Calcification, Serum Phosphorus, and Kidney Function

Cited by 94 publications

References 27 publications

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Vascular Toxicity of Phosphate in Chronic Kidney Disease

Fibroblast Growth Factor 23

Papel Do Fosfato Na Doença Cardiovascular: Marcador Ou Causador De Lesão?

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