A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD)

Toussaint, Nigel D; Pedagogos, Eugenia; Lioufas, Nicole; Elder, Grahame J.; Pascoe, Elaine M.; Badve, Sunil V.; Valks, Andrea; Block, Geoffrey A.; Boudville, Neil; Cameron, James D.; Campbell, Katrina L.; Chen, Sylvia S. M.; Faull, Randall J.; Holt, Stephen; Jackson, D.; Jardine, Meg; Johnson, David W.; Kerr, Peter G.; Lau, Kenneth; Hooi, Lai Seong; Narayan, Om; Perkovic, Vlado; Polkinghorne, Kevan R.; Pollock, Carol; Reidlinger, Donna; Robison, Laura; Smith, Edwin R.; Walker, Robert; Wang, Angela Yee-Moon; Hawley, Carmel M.; Investigators, Improve-Ckd Trial

doi:10.1681/asn.2020040411

Cited by 63 publications

(67 citation statements)

References 35 publications

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“…In dialysis patients, higher CRP levels are predictive for cardiovascular events [ 71 ], while the use of Pi binders is associated with reduced levels of the inflammatory markers CRP and IL-6 [ 72 ]. However, Pi binders failed to lower serum Pi levels and attenuate aortic stiffness in CKD stage 3b–4 patients [ 73 ]. Nevertheless, Fetuin-A could be down-regulated during inflammation and was negatively associated with CRP levels and increased all-cause and cardiovascular mortality in hemodialysis patients [ 74 ].…”

Section: Control Of Inorganic Phosphate and Calcium Balancementioning

confidence: 99%

“…Pi-restricting diets are effective in lowering blood Pi levels and associated biochemical markers, but their implementation is often difficult when trying to avoid too strong protein restriction in patients with advanced CKD. Pi binders may provide at best modest reductions in serum Pi and FGF23 levels and a recent well-controlled clinical trial assessing vascular stiffness through pulse-wave velocity as primary outcome failed to demonstrate efficacy, while bill burden and costs for this therapy are high [ 73 , 251 ]. More recently, tenapanor, a substance reducing paracellular intestinal Pi absorption, has been shown to reduce plasma Pi levels, but its effects on relevant clinical outcomes have not been tested to date [ 250 , 252 , 253 ].…”

Section: Therapies To Prevent or Reduce Vascular Calcificationmentioning

confidence: 99%

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Inflammation: a putative link between phosphate metabolism and cardiovascular disease

et al. 2021

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Dietary habits in the western world lead to increasing phosphate intake. Under physiological conditions, extraosseous precipitation of phosphate with calcium is prevented by a mineral buffering system composed of calcification inhibitors and tight control of serum phosphate levels. The coordinated hormonal regulation of serum phosphate involves fibroblast growth factor 23 (FGF23), αKlotho, parathyroid hormone (PTH) and calcitriol. A severe derangement of phosphate homeostasis is observed in patients with chronic kidney disease (CKD), a patient collective with extremely high risk of cardiovascular morbidity and mortality. Higher phosphate levels in serum have been associated with increased risk for cardiovascular disease (CVD) in CKD patients, but also in the general population. The causal connections between phosphate and CVD are currently incompletely understood. An assumed link between phosphate and cardiovascular risk is the development of medial vascular calcification, a process actively promoted and regulated by a complex mechanistic interplay involving activation of pro-inflammatory signalling. Emerging evidence indicates a link between disturbances in phosphate homeostasis and inflammation. The present review focuses on critical interactions of phosphate homeostasis, inflammation, vascular calcification and CVD. Especially, pro-inflammatory responses mediating hyperphosphatemia-related development of vascular calcification as well as FGF23 as a critical factor in the interplay between inflammation and cardiovascular alterations, beyond its phosphaturic effects, are addressed.

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Section: Control Of Inorganic Phosphate and Calcium Balancementioning

confidence: 99%

Section: Therapies To Prevent or Reduce Vascular Calcificationmentioning

confidence: 99%

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

et al. 2021

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“…However, these trials included small numbers of patients and did not have long-term follow-up. Sevelamer could lead to a reduction in vascular calcification vs. calcium-based phosphate binders [ 71 ]. The advantages and disadvantages of phosphate chelators are summarized in Table 1 .…”

Section: Phosphate Bindersmentioning

confidence: 99%

Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins

Laville

Massy

Kamel

et al. 2021

Toxins

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Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota’s activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.

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“…Newer classes of phosphate binders, including lanthanum carbonate and sevelamer, have been anecdotally shown to retard coronary artery calcification and modestly lower pulse wave velocity in CKD and ESRD patients [ 56 , 57 ], as well as mortality in CKD patients [ 58 ]. However, their ability to slow the extent of VC seems lost in those with normal serum phosphate levels, casting doubt on the exact efficacy of these newer non-calcium phosphate binders [ 59 ]. Iron citrate, a more recent member of phosphate binders, ameliorates vascular calcification through decreasing gastrointestinal phosphate availability and absorption in animal models of CKD and potentially in clinical settings [ 60 ].…”

Section: Gastrointestinal Decontamination For Toxin Removal and Vcmentioning

confidence: 99%

Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

Chao

Lin

2020

Toxins

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Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.

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A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD)

Cited by 63 publications

References 35 publications

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins

Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

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