Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho

Yamada, S.; Giachelli, Cecilia M.

doi:10.1016/j.bone.2016.11.012

Cited by 238 publications

(204 citation statements)

References 101 publications

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“…Serum α-Klotho predicts the progression of CKD,29 besides it is associated to arterial stiffness30 and plays a major role in protecting against VC 31. Moreover, Klotho-hypomorphic mice suffer from VC 32…”

Section: Discussionmentioning

confidence: 99%

Fractional excretion of phosphorus and vascular calcification in stage 3 chronic kidney disease

Villodres

Gutiérrez

Frías

et al. 2019

Journal of Investigative Medicine

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The role of renal excretion of Pi in relation to vascular calcification (VC) in patients in the early stages of chronic kidney disease (CKD) is controversial. Thus, we determine the relation between fractional excretion of phosphorus (FEP) and VC, measured using two methods in a cross-sectional study of patients with stage 3 CKD. We recorded demographic data, anthropometry, comorbidities and active treatment. We measured 24-hour urine FEP and, in serum, measured fibroblast growth factor 23 (FGF23), α-Klotho, intact parathyroid hormone (iPTH), calcium and phosphorus. VC was measured by lateral abdominal radiography (Kauppila index (KI)) and CT of the abdominal aorta (measured in Agatston units). In 57% of subjects, abnormal VC was present when measured using CT, and in only 17% using lateral abdominal radiography. Factors associated with VC using CT were age, cardiovascular risk factors, vascular comorbidity, microalbuminuria and levels of FGF23, phosphorus and calcium x phosphorus product (CaxP); although only age (OR 1.25, 95% CI 1.11 to 1.41), smoking (OR 21.2, CI 4.4 to 100) and CaxP (OR 1.21, CI 1.06 to 1.37) maintained the association in a multivariate analysis. By contrast, only age (OR 1.35, 95% CI 1.07 to 1.74), CaxP (OR 1.14, CI 1.13 to 1.92) and FEP (OR 1.07,95% CI 1004 to 1.14) were associated with abnormal VC in the lateral abdominal radiography. In conclusion, in patients with stage 3 CKD, the detection of VC by abdominal CT is more sensitive than conventional X-rays. Moreover, CaxP is associated with cardiovascular risk factors and vascular comorbidity; quantification of FEPi in these patients provides additional clinical information in advanced VC detected by KI.

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Section: Discussionmentioning

confidence: 99%

Fractional excretion of phosphorus and vascular calcification in stage 3 chronic kidney disease

Villodres

Gutiérrez

Frías

et al. 2019

Journal of Investigative Medicine

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“…Vascular calcification (VC) is very common and, at present, it is one of the main complications of CKD, which increases the CVD related mortality . The formation of VC is associated with complex pathological mechanisms, including osteochondral differentiation and apoptosis of vascular smooth muscle cells (VSMCs), instability and release of extracellular vesicles loaded calcium and phosphate . Among the various causes in CKD, abnormal deposition of calcium phosphate (Pi) salt is most closely related to VC .…”

Section: Introductionmentioning

confidence: 99%

“…Patients with chronic kidney disease (CKD) show an increasing risk of severe cardiovascular diseases (CVD). 1,2 Cardiovascular diseases account for 30% to 50% of all-cause mortality in patients with CKD and end-stage kidney disease worldwide. 3,4 Although various risk factors contributed to cardiovascular complications are well recognized during the development of CKD, it is still unable to explain the specific molecular mechanisms of placing a premium on cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 The formation of VC is associated with complex pathological mechanisms, including osteochondral differentiation and apoptosis of vascular smooth muscle cells (VSMCs), instability and release of extracellular vesicles loaded calcium and phosphate. 1,7 Among the various causes in CKD, abnormal deposition of calcium phosphate (Pi) salt is most closely related to VC. 8 It has been proved that elevated serum Pi is a risk factor for VC and cardiovascular mortality and morbidity among CKD populations in clinical studies.…”

Section: Introductionmentioning

confidence: 99%

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Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

Chen

Huang

Duan

et al. 2019

The Kaohsiung J of Med Scie

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Vascular calcification (VC) plays as a critical role on cardiovascular disease (CVD) and acts as a notable risk factor in cardiovascular system. Vascular smooth muscle cells (VSMCs) calcification can be triggered by high phosphate treatment; however, the explicit mechanism remains unclear. In the present study, we isolated VSMCs from primary rat artery, applied β‐GP (β‐glycerophosphate) for inducing VSMCs calcification in vitro to explore the mechanism of phosphate‐induced calcification in VSMCs. Alizarin red staining was performed to assess the mineralization in VSMCs. Calcium deposition experiment was taken to evaluate the calcium content. ALP staining was determined to assess the ALP activity. The recombinant adenoviruses were constructed for the overexpression of Klotho and FGF23, respectively. qRT‐PCR and western blot analysis were subjected to measure the expression of Klotho/FGF23 and correlated genes among Wnt7b/β‐catenin pathway. We found that the calcium content was obviously increased and Alizarin red staining was positive in calcification group exposure with high phosphate in a time‐dependent manner. The expression of Klotho and FGF23 was significantly decreased in the calcification group. However, overexpression of Klotho and FGF23 markedly reversed VSMCs calcification stimulating with high phosphate treatment. Moreover, Wnt7b/β‐catenin inhibitor DKK1 could partly attenuate the effect of high phosphate on calcified VSMCs. These findings demonstrated that Klotho/FGF23 axis could modulate high phosphate‐induced VSMCs calcification via Wnt7b/β‐catenin signaling pathway. Our findings unravel that Klotho/FGF23‐ Wnt7b/β‐catenin axis functions as a crucial role in the VSMCs calcification.

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“…In addition to microvascular medial calcifications, a skin biopsy can also show thrombosis, suggesting additional endothelial dysfunction. Apart from traditional risk factors for vascular calcification (age, obesity, gender, hypertension, diabetes, smoking, hypercholesterolemia), CPX can be caused by an imbalance between promotors of vascular calcification (calcium salts and vitamin D intake, hyperphosphatemia, calcium × phosphorus product, elevated parathyroid hormone [PTH], systemic inflammation) and inhibitors of vascular calcification (fetuin A, matrix GLA protein [MGP], osteocalcin, FGF-23, Klotho) [9-11]. The use of vitamin K antagonists and cases of vitamin K deficiency have also emerged as major causes of vascular calcification [12].…”

Section: Introductionmentioning

confidence: 99%

The Effectiveness of Topical Cerium Nitrate-Silver Sulfadiazine Application on Overall Outcome in Patients with Calciphylaxis

Darres¹,

Delaval²,

Fournier³

et al. 2019

Dermatology

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Background: Calciphylaxis (CPX) is a rare and life-threatening disease characterized by vascular calcification and development of painful and necrotizing skin lesions with a challenging management. Mechanisms of CPX are complex and include an imbalance between vascular calcification promoters and inhibitors, and frequently vitamin K deficiency. Objectives: To describe the various presentations and identify predictive factors of death in patients with CPX. Methods: In this multicenter retrospective study, we included 71 CPX patients followed in South-West France (n = 26) and in French Polynesia (n = 45), and who all received sodium thiosulfate (25 g thrice weekly for a median of 61 days). Results: Characteristics at presentation significantly differed between metropolitan and Polynesian French patients. Polynesians were less frequently on regular dialysis at the onset of CPX, had a higher incidence of diabetes mellitus and obesity, more disturbances of calcium-phosphorus metabolism, and received vitamin K antagonists less frequently than patients from South-West France. Despite intensive management, the 1-year mortality rate was 66% and median time to death was 200 days (IQR, 40; 514). The number of body areas involved (i.e., three: OR 2.70 [1.09; 6.65], p = 0.031; four: OR 8.79 [1.54; 50.29], p = 0.015) was the only predictive factor for death, whereas application of topical cerium nitrate-silver sulfadiazine was protective (OR 0.44 [0.20; 0.99], p = 0.046). Surgical debridement, hyperbaric oxygenation therapy, and geographical origin were not associated with overall outcomes. Conclusions: Cerium nitrate may lead to vascular decalcification and chelation of reactive oxygen species, and prevent infection. Cerium nitrate-silver sulfadiazine was associated with better outcomes and should be tested in a prospective comparative trial in CPX patients.

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Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho

Cited by 238 publications

References 101 publications

Fractional excretion of phosphorus and vascular calcification in stage 3 chronic kidney disease

Fractional excretion of phosphorus and vascular calcification in stage 3 chronic kidney disease

Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

The Effectiveness of Topical Cerium Nitrate-Silver Sulfadiazine Application on Overall Outcome in Patients with Calciphylaxis

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