Aortic Calcification and Arterial Stiffness Burden in a Chronic Kidney Disease Cohort with High Cardiovascular Risk: Baseline Characteristics of the Impact of Phosphate Reduction On Vascular End-Points in Chronic Kidney Disease Trial

2020 ◽  
Vol 51 (3) ◽  
pp. 201-215 ◽  
Author(s):  
Nicole M. Lioufas ◽  
Eugenia Pedagogos ◽  
Carmel M. Hawley ◽  
Elaine M. Pascoe ◽  
Grahame J. Elder ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Waist Circumference ◽  
Kidney Disease ◽  
Arterial Stiffness ◽  
Serum Phosphate ◽  
Older Age ◽  
End Points ◽  
High Baseline ◽  
Fgf 23 ◽  
The Impact

Chronic kidney disease (CKD) is associated with excess cardiovascular morbidity and mortality compared to the general population. Hyperphosphataemia, associated with vascular calcification and arterial stiffness, may play a key role in the pathogenesis of cardiovascular disease (CVD) associated with CKD, although phosphate reduction strategies have not consistently proven to beneficially affect clinically relevant outcomes. The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) study is an international, multi-centre, randomized, placebo-controlled trial investigating the effect of the phosphate binder lanthanum carbonate on intermediate cardiovascular markers in patients with stage 3b–4 CKD. The primary end-point is change in carotid-femoral pulse wave velocity (PWV, SphygmoCor) after 96 weeks. Secondary outcomes include change in abdominal aortic calcification (AAC, computed tomography), serum phosphate and fibroblast growth factor 23 (FGF-23). In total, 278 participants were recruited and randomized, mean age 63 ± 13 years, 69% male, 45% diabetes, 32% CVD, 33% stage 3b CKD and 67% stage 4 CKD. Mean estimated glomerular filtration rate and serum phosphate were 26.6 ± 8.3 mL/min/1.72 m2 and 1.25 ± 0.20 mmol/L, respectively. Median (interquartile range) intact and c-terminal FGF-23 levels were 133.0 (89.1–202) pg/mL and 221.1 (154.3–334.1) RU/mL, respectively. Mean PWV was 10.8 ± 3.6 m/s and 81% had AAC (median Agatston score 1,535 [63–5,744] Hounsfield units). PWV ≥10 m/s was associated with older age, diabetes, CVD, presence of AAC, higher systolic blood pressure (BP), larger waist circumference and higher alkaline phosphatase. AAC was associated with older age, male sex, diabetes, CVD, higher diastolic BP, dyslipidaemia (and use of statins), smoking, larger waist circumference and increased PWV. In conclusion, IMPROVE-CKD participants had high baseline risk for cardiovascular events, as suggested by high baseline PWV and AAC values.

scholarly journals Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD? Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study

BMJ Open ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. e024382 ◽  
Author(s):  
Nicole Lioufas ◽  
Nigel D Toussaint ◽  
Eugenia Pedagogos ◽  
Grahame Elder ◽  
Sunil V Badve ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Arterial Compliance ◽  
Left Ventricular ◽  
Serum Phosphate ◽  
Lanthanum Carbonate ◽  
Cardiovascular Morbidity And Mortality ◽  
Fgf 23 ◽  
The Impact

IntroductionPatients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD.Methods and analysisWe outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population—the IMpact of Phosphate Reduction On Vascular End-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels.Ethics and disseminationEthical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences.Trial registration numberACTRN12610000650099.

scholarly journals Fibroblast Growth factor 23 and α-Klotho protein are associated with adverse clinical outcomes in non dialysis chronic kidney disease stage 1-5 patients

2019 ◽  
Author(s):  
Eleni Manou ◽  
Elias Thodis ◽  
George Arsos ◽  
Ploumis Pasadakis ◽  
Stylianos Panagoutsos ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Regression Analysis ◽  
Growth Factor ◽  
Kidney Disease ◽  
Fibroblast Growth Factor 23 ◽  
Serum Phosphate ◽  
Fibroblast Growth ◽  
Fgf 23 ◽  
Stage 1

Abstract Background: Fibroblast Growth Factor 23 (FGF-23) and α-Klotho contribute to the patho-genesis of chronic kidney disease - mineral and bone disorders (CKD-MBD). The aim of our study was to evaluate the association of FGF-23 and α-Klotho levels with CKD-MBD parameters, as well as with renal prognosis and mortality, in CKD patients stage 1-5, not in renal replacement therapy (RRT). Methods: 128 patients were included. At enrollment GFR was measured (mGFR) and plasma levels of carboxyl terminal FGF-23 (cFGF-23) and soluble α-Klotho (sKlotho) were determined by ELISA. Abdominal aorta calcification (AAC) score was assessed in lateral abdominal X ray. The composite end point (event) was initiation of RRT or death. Follow-up was five years (median 36, range 2-60 months). Results: mGFR significantly correlated with cFGF-23 and sKlotho negatively and posi-tievely respectively (p<0.0001 for both). Multiple regression analysis showed an inde-pendent correlation of cFGF-23 with mGFR, 25-OH vitamin D, presence of diabetes melli-tus and AAC score, of sKlotho with mGFR and phosphate and of AAC score with sKlotho and cFGF-23. Multivariate regression tree analysis, led to the formation of three regression groups (A, B, C) based on two “cut off” values: mGFR levels of 60.85 ml/min/1.73m2 and serum phosphate levels of 3.7 mg/dl. These groups significantly correlated with the five CKD stages and additionally cFGF-23 and sKlotho plasma levels (p<0.0001 for both). During follow-up, 40 out of the 128 patients, (31.2%) either initiated RRT or died (31 and 9 respectively). Kaplan Meier survival analysis showed that groups of patients with cFGF-23 levels less than median and those with sKlotho more than median value showing a more favorable course, regarding outcome (p=0.0003 for cFGF-23, p=0.004 for s-Klotho). In Cox regression analysis the association of cFGF-23 (p=0.04), sKlotho (p=0.008) and AAC score (p=0.01) with the presence of “event” remained significant after adjustment for traditional and CKD- related covariates. Conclusions: In CKD patients stage 1-5, cFGF-23 and sKlotho levels are associated with adverse clinical outcomes. mGFR and serum phosphate, in association with sKlotho lev-els, may provide a “new classification” of CKD patients, which appears to be predictive of outcome.

The effect of interactions between proteinuria, activity of fibroblast growth factor 23 and serum phosphate on renal progression in patients with chronic kidney disease: a result from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease study

2019 ◽  
Vol 35 (3) ◽  
pp. 438-446 ◽  
Author(s):  
Hyoungnae Kim ◽  
Jimin Park ◽  
Ki Heon Nam ◽  
Jong Hyun Jhee ◽  
Hae-Ryong Yun ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Significant Interaction ◽  
Independent Risk Factor ◽  
Fibroblast Growth Factor 23 ◽  
Serum Phosphate ◽  
Ckd Progression ◽  
Biologic Activity ◽  
Renal Progression ◽  
Fgf 23

Abstract Background Recent experimental study reported that proteinuria increases serum phosphate by decreasing biologic activity of fibroblast growth factor 23 (FGF-23). We examined this relationship in a large chronic kidney disease (CKD) cohort and evaluated the combined effect of proteinuria, FGF-23 activity and serum phosphate on CKD progression. Methods The activity of FGF-23, measured by the fractional excretion of phosphate (FEP)/FGF-23 ratio, was compared according to the degree of proteinuria in 1909 patients with CKD. Primary outcome was CKD progression defined as ≥50% decline of estimated glomerular filtration rate, doubling of serum creatinine and start of dialysis. Results There was a negative relationship between 24-h urine protein (24-h UP) and FEP/FGF-23 ratio (γ −0.07; P = 0.005). In addition, after matching variables associated with serum phosphate, patients with more proteinuria had higher serum phosphate (P &lt; 0.001) and FGF-23 (P = 0.012), and lower FEP/FGF-23 ratio (P = 0.007) compared with those with less proteinuria. In the matched cohort, low FEP/FGF-23 ratio was an independent risk factor for CKD progression (hazard ratio 0.87 per 1 log increase; 95% confidence interval 0.79–0.95; P = 0.002), and there was significant interaction between 24-h UP and FEP/FGF-23 ratio (P = 0.039). Furthermore, 24-h UP and serum phosphate also had a significant interaction on CKD progression (P &lt; 0.001). Conclusions Proteinuria is associated with decreased biologic activity of FGF-23 and increased serum phosphate. Furthermore, diminished activity of FGF23 is an independent risk factor for renal progression in proteinuric CKD patients.

Predicting the risk of severe myocardial infarction in patientswith chronic 5D-stage kidneydisease and mineral-bone disorders

2020 ◽  
Vol 24 (5) ◽  
pp. 51-57
Author(s):  
A. M. Mambetova ◽  
Sh. N. Gutareva ◽  
I. L. Semyonova ◽  
A. Sh. Kegaduev
Keyword(s):  
Myocardial Infarction ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Bone Mineral ◽  
Heart Valves ◽  
Clinical Manifestations ◽  
Aortic Calcification ◽  
Bone Disorders ◽  
Fgf 23 ◽  
The Impact

BACKGROUND. The increasing prevalence of chronic kidney disease is a global trend as well in general as in terminal kidney failure in particular. Of great interest is the analysis of the impact of mineral and bone disorders on the risk of cardiovascular complications and, first of all, acute myocardial infarction (AMI ). THE AIM: to assess the impact of bone mineral disorders on the risk of AMI in patients with stage 5D chronic kidney disease. PATIENTS AND METHODS. It was conducted a prospective (three-year) cohort study of 85 patients with CKD S5D treated with programmed hemodialysis. At the first stage, it were reg­istered the risk factors and clinical manifestations of CKD 5 St, as well as indicators that characterized bone mineral disorders (levels of blood inorganic phosphate, calcium, parathyroid hormone, 1,25(OH)D, fibroblast growth factor (FGF-23), a-Klotho). Signs of calcification of the heart valves and aortic wall were also determined. The second stage involved a re-examination of patients after 3.1±0.1 years, as well as registration of endpoints, which were identified as cases of fatal and non-fatal AMI. RESULTS. After 3 years of follow-up, the following endpoints were registered: nonfatal AMI - 6 cases, fatal AMI-4 cases. The risk of AMI increased in the presence of initial persistent hyperphosphatemia and 1,25(OH)D3 deficiency, as well as calcifica­tion of heart valves and high FGF-23 values, but only in combination with hyperphosphatemia and 1,25(OH)D3 deficiency. Hyperparathyroidism also increased the risk of AMI in conditions of a deficit of 1,25(OH)D3. The risk of nonfatal AMI cases was also increased by the presence of aortic calcification and its severity. The risk of AMI increases in the presence of initial persistent hyperphosphatemia and a deficit of 1.25 (OH)D3, as well as CCS, high FGF-23 values, but only in combination with hyperphosphatemia and a deficit of 1.25(OH)D3. Hyperparathyroidism also increases the risk of AMI in conditions of a deficit of 1.25(OH)D3. The risk of nonfatal cases of AMI also increases the presence of aortic calcification and its severity. CONCLU­SION. The risk of AMI increases in the presence of initial persistent hyperphosphatemia and a deficit of 1,25(OH)D3, as well as calcification of the heart valves, high FGF-23 values, but only in combination with hyperphosphatemia and a deficit of 1,25(OH) D3. Hyperparathyroidism also increases the risk of AMI in conditions of a deficit of 1.25(OH)D3. The risk of nonfatal cases of AMI also increases the presence of aortic calcification.

scholarly journals A survival analysis of COVID-19 in the Mexican population

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Guillermo Salinas-Escudero ◽  
María Fernanda Carrillo-Vega ◽  
Víctor Granados-García ◽  
Silvia Martínez-Valverde ◽  
Filiberto Toledano-Toledano ◽  
...  
Keyword(s):  
Public Health ◽  
Chronic Kidney Disease ◽  
Survival Analysis ◽  
Kidney Disease ◽  
Health Services ◽  
Older Age ◽  
Mexican Population ◽  
Public Health Services ◽  
Risk Of Death ◽  
The Impact

Abstract Background At present, the Americas report the largest number of cases of COVID-19 worldwide. In this region, Mexico is the third country with most deaths (20,781 total deaths). A sum that may be explained by the high proportion of people over 50 and the high rate of chronic diseases. The aim of this analysis is to investigate the risk factors associated with COVID-19 deaths in Mexican population using survival analysis. Methods Our analysis includes all confirmed COVID-19 cases contained in the dataset published by the Epidemiological Surveillance System for Viral Respiratory Diseases of the Mexican Ministry of Health. We applied survival analysis to investigate the impact of COVID-19 on the Mexican population. From this analysis, we plotted Kaplan-Meier curves, and constructed a Cox proportional hazard model. Results The analysis included the register of 16,752 confirmed cases of COVID-19 with mean age 46.55 ± 15.55 years; 58.02% (n = 9719) men, and 9.37% (n = 1569) deaths. Male sex, older age, chronic kidney disease, pneumonia, hospitalization, intensive care unit admission, intubation, and health care in public health services, were independent factors increasing the risk of death due to COVID-19 (p < 0.001). Conclusions The risk of dying at any time during follow-up was clearly higher for men, individuals in older age groups, people with chronic kidney disease, and people hospitalized in public health services.

scholarly journals Relationship between Fibroblast Growth Factor-23 and Mineral Metabolism in Chronic Kidney Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Kosaku Nitta
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Left Ventricular ◽  
Serum Phosphate ◽  
Maintenance Hemodialysis ◽  
Fibroblast Growth ◽  
Fgf 23

Fibroblast growth factor- (FGF-)23 is a recently discovered regulator of calcium-phosphate metabolism. FGF-23 appears to decrease in synthesis and accelerated degradation of 1,25(OH)2D. Together with its cofactor Klotho, FGF-23 maintains serum phosphate levels within the normal range by increasing renal phosphate excretion. In chronic kidney disease (CKD), FGF-23 levels rise in parallel with the decline in renal function long before a significant increase in serum phosphate concentration occurs. Both Klotho and FGF-23, linked by a receptor mechanism, affect vitamin D synthesis and parathyroid hormone (PTH) secretion. Previous studies have shown a close association between reduced FGF-23 or Klotho activities and vascular calcification. The possible association of FGF-23 and left ventricular hypertrophy or vascular dysfunction has been proposed. Finally, prospective studies have shown that high serum FGF-23 concentrations predict more rapid disease progression in CKD patients who were not on dialysis and increased mortality in patients on maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target for the management of CKD.

scholarly journals Effect of paricalcitol and cinacalcet on serum phosphate, FGF-23, and bone in rats with chronic kidney disease

2010 ◽  
Vol 298 (6) ◽  
pp. F1315-F1322 ◽  
Author(s):  
Jane L. Finch ◽  
Masanori Tokumoto ◽  
Hironori Nakamura ◽  
Wei Yao ◽  
Mohammad Shahnazari ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Parathyroid Hormone ◽  
Kidney Disease ◽  
Bone Volume ◽  
Serum Phosphate ◽  
Dialysis Patients ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Osteoid Surface ◽  
Fgf 23

Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3–4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances “equivalent” to patients with CKD 3–4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg·kg−1·day−1 po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 μg/kg, 3 × wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca × P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)2D3 was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)2D3, and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.

scholarly journals Changes in FGF-23, Neutrophil/Platelet Activation Markers, and Angiogenin in Advanced Chronic Kidney Disease and Their Effect on Arterial Stiffness

2019 ◽  
Vol 44 (5) ◽  
pp. 1166-1178
Author(s):  
Hye-Min Choi ◽  
Young-Eun Kwon ◽  
Sol Kim ◽  
Dong-Jin Oh
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Arterial Stiffness ◽  
Platelet Activation ◽  
Activation Markers ◽  
Stage 4 ◽  
Ckd Stage ◽  
The Mean ◽  
Fgf 23

Aims: The aims of this study were to measure changes in fibroblast growth factor 23 (FGF-23), neutrophil (elastase, lactoferrin)/platelet activation marker (mean platelet volume-to-platelet count ratio [MPR]), and angiogenin according to the stage of chronic kidney disease (CKD), and to evaluate the association of FGF-23, elastase, lactoferrin, MPR, and angiogenin with arterial stiffness using brachial-ankle pulse wave velocity (ba-PWV) in CKD patients. Methods: According to the estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the patients were allocated to five groups: (1) normal controls (eGFR ≥90 mL/min/1.73 m2 without pathologic, urine [proteinuria], blood [electrolyte], and imaging abnormalities; n = 22); (2) CKD stage 2 (eGFR 60–89 mL/min/1.73 m2; n = 17); (3) CKD stage 3 (eGFR 30–59 mL/min/1.73 m2; n = 22); (4) CKD stage 4 (eGFR 15–30 mL/min/1.73 m2; n = 17); and (5) CKD stage 5-hemodialysis (HD) (n = 30). All the patients were free of clinically apparent cardiovascular disease. Serum FGF-23, elastase, lactoferrin, and angiogenin concentrations and the MPR were measured to study the association of the above parameters with the clinical (age, sex, presence of diabetes mellitus, and blood pressure), biochemical (calcium, phosphorus, uric acid, intact parathyroid hormone [PTH], low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein), and ba-PWV values of the CKD patients. Results: (1) The mean ba-PWV values were 1,497.2 ± 206.4 cm/s in the controls, 1,649.0 ± 247.9 cm/s in the CKD stage 2 group (p < 0.05 vs. controls), 1,655.8 ± 260.3 cm/s in the CKD stage 3 group (p < 0.05 vs. controls), 1,823.0 ± 402.4 cm/s in the CKD stage 4 group (p < 0.05 vs. controls and CKD stages 2 and 3), and 1,905.2 ± 374.1 cm/s in the CKD stage 5-HD group (p < 0.05 vs. controls and CKD stage 2). (2) The mean log10(FGF-23) concentration values were 0.77 ± 0.27, 0.97 ± 0.48, 1.10 ± 0.35 (p < 0.05 vs. controls and CKD stage 2), 1.35 ± 0.48 (p < 0.05 vs. controls and CKD stages 2 and 3), and 2.12 ± 0.82 (p < 0.05 vs. controls and CKD stages 2–4); the mean angiogenin levels were 230.6 ± 70.5 pg/mL, 283.0 ± 53.5 pg/mL (p < 0.05 vs. controls), 347.3 ± 76.9 pg/mL (p < 0.05 vs. controls and CKD stage 2), 445.9 ± 90.6 pg/mL (p < 0.05 vs. controls and CKD stages 2 and 3), and 370.9 ± 142.4 pg/mL (p < 0.05 vs. controls and CKD stages 2 and 3). (3) In the stage 3–4 CKD/HD patients, the mean elastase-to-neutrophil and lactoferrin-to-neutrophil ratios were significantly lower than in the controls and the stage 2 CKD patients. (4) Our multivariate linear regression analyses showed that age, pulse pressure, mean arterial pressure, PTH, and FGF-23 were independently associated with ba-PWV values. Conclusions: Circulating FGF-23 and angiogenin concentrations gradually increased as CKD advanced, whereas neutrophil activation markers were significantly lower in the stage 3–4 CKD/HD patients than in the controls and stage 2 CKD patients. FGF-23 was weakly associated with ba-PWV values in patients with CKD/HD and no previous cardiovascular disease.

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