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BACKGROUND: Abnormalities of fibroblast growth factor-23 (FGF-23) plasma levels predict adverse outcomes in patients with coronary artery disease. However, FGF-23 has a different behaviour in the presence of type 2 diabetes mellitus (T2D). We explored whether the presence of T2D affects the predictive power of FGF-23. METHODS: In 704 patients with stable coronary artery disease, FGF-23, calcidiol, parathormone (PTH) and phosphate plasma levels were prospectively assessed. The primary outcome was the development of acute ischemic events (acute coronary syndrome, stroke or transient ischemic attack), heart failure or death. RESULTS: One hundred seventy-three (24.6%) patients had T2D, without differences in age, sex or estimated glomerular filtration rate as compared with non-diabetic patients. Serum PTH was lower and phosphate higher in T2D than in non-diabetic patients, without differences in FGF-23 or calcidiol levels. During follow-up (2.15 ± 0.99 years), 26 (15.2%) T2D and 51 (9.6%) non-diabetic patients developed the outcome (p = 0.048). T2D patients who developed the outcome had higher FGF-23 [112.0 (59.9, 167.6) vs 68.9 (54.2, 93.0) RU/mL; p = 0.002], PTH [71.3 (47.3, 106.6) vs 51.9 (40.8, 66.2) pg/mL; p = 0.004) and phosphate (3.53 ± 0.71 vs 3.25 ± 0.50 mg/dL; p = 0.017) levels than T2D subjects who remained stable. These differences were not significant in non-diabetic patients. By multivariable Cox proportional hazard model, FGF-23 predicted independently the outcome in T2D patients [hazard ratio = 1.277; 95% CI (1.132, 1.442)] but not in those without T2D. CONCLUSIONS: FGF-23 plasma levels predict adverse cardiovascular outcomes in coronary artery disease patients who have T2D but not in those without T2D. This finding should be confirmed in larger studies. Copyright © 2016 John Wiley & Sons, Ltd.
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Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/complicações , Fatores de Crescimento de Fibroblastos/sangue , Calcifediol/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Fator de Crescimento de Fibroblastos 23 , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Prognóstico , Estudos ProspectivosRESUMO
Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is characterized by increased circulating levels of parathormone (PTH) and fibroblast growth factor 23 (FGF23), bone disease, and vascular calcification, and is associated with adverse outcomes. We studied the prevalence of mineral metabolism disorders, and the potential relationship between decreased estimated glomerular filtration rate (eGFR) and CKD-MBD in coronary artery disease patients in a cross-sectional study of 704 outpatients 7.5 ± 3.0 months after an acute coronary syndrome. The mean eGFR (CKD Epidemiology Collaboration formula) was 75.8 ± 19.1 ml/min/1.73 m(2). Our patients showed lower calcidiol plasma levels than a healthy cohort from the same geographical area. In the case of men, this finding was present despite similar creatinine levels in both groups and older age of the healthy subjects. Most patients (75.6 %) had an eGFR below 90 ml/min/1.73 m(2) (eGFR categories G2-G5), with 55.3 % of patients exhibiting values of 60-89 ml/min/1.73 m(2) (G2). PTH (r = -0.3329, p < 0.0001) and FGF23 (r = -0.3641, p < 0.0001) levels inversely correlated with eGFR, whereas calcidiol levels and serum phosphate levels did not. Overall, PTH levels were above normal in 34.9 % of patients. This proportion increased from 19.4 % in G1 category patients, to 33.7 % in G2 category patients and 56.6 % in G3-G5 category patients (p < 0.001). In multivariate analysis, eGFR and calcidiol levels were the main independent determinants of serum PTH. The mean FGF23 levels were 69.9 (54.6-96.2) relative units (RU)/ml, and 33.2 % of patients had FGF23 levels above 85.5 RU/ml (18.4 % in G1 category patients, 30.0 % in G2 category patients, and 59.2 % in G3-G5 category patients; p < 0.001). In multivariate analysis, eGFR was the main predictor of FGF23 levels. Increased phosphate levels were present in 0.7 % of the whole sample: 0 % in G1 category patients, 0.3 % in G2 category patients, and 2.8 % in G3-G5 category patients (p = 0.011). Almost 90 % of patients had calcidiol insufficiency without significant differences among the different degrees of eGFR. In conclusion, in patients with coronary artery disease there is a large prevalence of increased FGF23 and PTH levels. These findings have an independent relationship with decreased eGFR, and are evident at an eGFR of 60-89 ml/min/1.73 m(2). Then, mild decreases in eGFR must be taken in consideration by the clinician because they are associated with progressive abnormalities of mineral metabolism.
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Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Doença da Artéria Coronariana/complicações , Taxa de Filtração Glomerular , Adulto , Idoso , Idoso de 80 Anos ou mais , Calcifediol/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/epidemiologia , Estudos Transversais , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: A positive calcium balance may contribute to vascular calcification, while a negative balance increases iPTH. We explored the impact of different dialysate calcium concentrations on bone and mineral metabolism parameters according to pre-dialysis serum calcium levels. RESULTS: Fifty-six hemodialysis patients were dialyzed with 3.0 or 2.5 mEq/l dialysate [calcium] in a crossover study of two weeks. Bone mineral metabolites were measured prior to and following the hemodialysis session. A 3.0 mEq/l dialysate [calcium] increased more post-dialysis total calcium and ionized calcium than 2.5 mEq/l dialysate [calcium]. The mildest dialysis-induced changes in calcium and PTH were observed in patients with pre-dialysis serum calcium <8.75 mg/dl dialyzed with 2.5 mEq/l dialysate [calcium] and in patients with pre-dialysis serum calcium >9.15 mg/dl dialyzed with 3.0 mEq/l calcium dialysate. CONCLUSION: In conclusion, the individualization of dialysate calcium concentration according to baseline pre-dialysis serum calcium may prevent major excursions in post-dialysis serum calcium and iPTH levels. SHORT SUMMARY: High calcium dialysate may increase serum calcium in hemodialysis patients, while low dialysate calcium may increase PTH. Individualization of dialysate calcium according to predialysis serum calcium levels may prevent or decrease unwanted excursions of both serum calcium and PTH.
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Cálcio/administração & dosagem , Soluções para Hemodiálise/química , Medicina de Precisão/métodos , Diálise Renal/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Cálcio/análise , Cálcio/sangue , Estudos Cross-Over , Feminino , Soluções para Hemodiálise/efeitos adversos , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/etiologia , Hipercalcemia/prevenção & controle , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/prevenção & controle , Hipocalcemia/diagnóstico , Hipocalcemia/etiologia , Hipocalcemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Estudos ProspectivosRESUMO
Bone is more than a reservoir of calcium and phosphorus. Its lacuno-canalicular arrangement provides an important pathway for exchange with circulation and currently, the skeleton is considered a large endocrine organ with actions that go beyond the control of calcium-phosphorus balance mediated by fibroblastic growth factor 23 (FGF23). Parallel to the modulating effect of adipokines on bone turnover, certain bone proteins, such as osteocalcin and sclerostin, play a counter-regulatory role on energy metabolism, probably in an attempt to ensure its high energy requirement for bone turnover. In this crosstalk between bone and other tissues, especially with adipose tissue, canonical Wnt/ß-catenin signaling is involved and therefore, sclerostin, an osteocyte derived protein that inhibits this signalling, emerges as a potential biomarker. Furthermore, its involvement in diverse pathologic conditions supports sclerostin as a therapeutic target, with an anti-sclerostin antibody recently approved in our country for the treatment of osteoporosis. This review addresses the endocrine nature of bone, the role of osteocalcin, and specially, the regulatory and modulatory role of sclerostin on bone turnover and energy homeostasis through its inhibitory effect on canonical Wnt/ß-catenin signaling, as well as its potential utility as a biomarker.
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Sarcopenia and dynapenia are two terms associated with ageing that respectively define the loss of muscle mass and strength. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) introduced the EWGSOP2 diagnostic algorithm for sarcopenia, which integrates both concepts. It consists of 4 sequential steps: screening for sarcopenia, examination of muscle strength, assessment of muscle mass and physical performance; depending on these last 3 aspects sarcopenia is categorised as probable, confirmed, and severe respectively. In the absence of validation of the EWGSOP2 algorithm in various clinical contexts, its use in haemodialysis poses several limitations: (a) low sensitivity of the screening, (b) the techniques that assess muscle mass are not very accessible, reliable, or safe in routine clinical care, (c) the sequential use of the magnitudes that assess dynapenia and muscle mass do not seem to adequately reflect the muscular pathology of the elderly person on dialysis. We reflect on the definition of sarcopenia and the use of more precise terms such as "myopenia" (replacing the classic concept of sarcopenia to designate loss of muscle mass), dynapenia and kratopenia. Prospective evaluation of EWGSOP2 and its comparison with alternatives (i.e. assessment of kratopenia and dynapenia only; steps 2 and 4) is proposed in terms of its applicability in clinical routine, resource consumption, identification of at-risk individuals and impact on events.
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Sarcopenia , Sarcopenia/diagnóstico , Humanos , Idoso , Força Muscular , Diálise Renal , Algoritmos , Terminologia como Assunto , Músculo Esquelético/fisiopatologiaRESUMO
AIMS: Abnormalities of mineral metabolism (MM) have been related to cardiovascular disorders. There are no reports on the prognostic role of MM after an acute coronary syndrome (ACS). We aim to assess the prognostic role of MM after an ACS. METHODS AND RESULTS: Plasma levels of components of MM [fibroblast growth factor 23 (FGF23), calcidiol, parathormone, klotho, and phosphate], high-sensitivity C-reactive protein, and N-terminal-pro-brain natriuretic peptide were measured in 1190 patients at discharge from an ACS. The primary outcome was a combination of acute ischaemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome. Age was 61.7 ± 12.2 years, and 77.1% were men. Median follow-up was 5.44 (3.03-7.46) years. Two hundred and ninety-four patients developed the primary outcome. At multivariable analysis FGF23 (hazard ratio, HR 1.18 [1.08-1.29], P < 0.001), calcidiol (HR 0.86 [0.74-1.00], P = 0.046), previous coronary or cerebrovascular disease, and hypertension were independent predictors of the primary outcome. The predictive power of FGF23 was homogeneous across different subgroups of population. FGF23 (HR 1.45 [1.28-1.65], P < 0.001) and parathormone (HR 1.06 1.01-1.12]; P = 0.032) resulted as independent predictors of HF. FGF23 (HR 1.21 [1.07-1.37], P = 0.002) and calcidiol (HR 0.72 [0.54-0.97), P = 0.028) were independent predictors of death. No biomarker predicted acute ischaemic events. FGF23 predicted independently the primary outcome in patients with estimated glomerular filtration rate > 60 mL/min/1.73 m2 . CONCLUSIONS: FGF23 and other components of MM are independent predictors of HF and death after an ACS. This effect is homogeneous across different subgroups of population, and it is not limited to patients with chronic kidney disease.
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Síndrome Coronariana Aguda , Insuficiência Cardíaca , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Coronariana Aguda/diagnóstico , Calcifediol , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Hormônio ParatireóideoRESUMO
Background: Mineral metabolism (MM), mainly fibroblast growth factor-23 (FGF-23) and klotho, has been linked to cardiovascular (CV) diseases. Cardiac rehabilitation (CR) has been demonstrated to reduce CV events, although its potential relationship with changes in MM is unknown. Methods: We performed a prospective, observational, case-control study, with acute coronary syndrome (ACS) patients who underwent CR and control patients (matched by age, gender, left ventricular ejection fraction, diabetes, and coronary artery bypass grafting), who did not. The inclusion dates were from August 2013 to November 2017 in CR group and from July 2006 to June 2014 in control group. Clinical, biochemical, and MM biomarkers were collected at discharge and six months later. Our objective was to evaluate differences in the modification pattern of MM in both groups. Results: We included 58 CR patients and 116 controls. The control group showed a higher prevalence of hypertension (50.9% vs. 34.5%), ST-elevated myocardial infarction (59.5% vs. 29.3%), and treatment with angiotensin-converting enzyme inhibitors (100% vs. 69%). P2Y12 inhibitors and beta-blockers were more frequently prescribed in the CR group (83.6% vs. 96.6% and 82.8% vs. 94.8%, respectively). After six months, klotho levels increased in CR patients whereas they were reduced in controls (+63 vs. -49 pg/mL; p < 0.001). FGF-23 was unchanged in the CR group and reduced in controls (+0.2 vs. -17.3 RU/dL; p < 0.003). After multivariate analysis, only the change in klotho levels was significantly different between groups (+124 pg/mL favoring CR group; IC 95% [+44 to +205]; p = 0.003). Conclusions: In our study, CR after ACS increases plasma klotho levels without significant changes in other components of MM. Further studies are needed to clarify whether this effect has a causal role in the clinical benefit of CR.
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As in 2011, when the Spanish Society of Nephrology (SEN) published the Spanish adaptation to the Kidney Disease: Improving Global Outcomes (KDIGO) universal Guideline on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), this document contains an update and an adaptation of the 2017 KDIGO guidelines to our setting. In this field, as in many other areas of nephrology, it has been impossible to irrefutably answer many questions, which remain pending. However, there is no doubt that the close relationship between the CKD-MBD/cardiovascular disease/morbidity and mortality complex and new randomised clinical trials in some areas and the development of new drugs have yielded significant advances in this field and created the need for this update. We would therefore highlight the slight divergences that we propose in the ideal objectives for biochemical abnormalities in the CKD-MBD complex compared to the KDIGO suggestions (for example, in relation to parathyroid hormone or phosphate), the role of native vitamin D and analogues in the control of secondary hyperparathyroidism and the contribution of new phosphate binders and calcimimetics. Attention should also be drawn to the adoption of important new developments in the diagnosis of bone abnormalities in patients with kidney disease and to the need to be more proactive in treating them. In any event, the current speed at which innovations are taking place, while perhaps slower than we might like, globally drives the need for more frequent updates (for example, through Nefrología al día).
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Doenças Ósseas Metabólicas , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Nefrologia , Insuficiência Renal Crônica , Humanos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/diagnóstico , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/diagnóstico , Minerais/uso terapêutico , FosfatosRESUMO
BACKGROUND: Parathormone (PTH) is a component of the Mineral Metabolism (MM) system that has been shown recently to add prognostic value in pts. with stable coronary artery disease (SCAD) and average renal function. However, the influence of renal function on the prognostic role of PTH in pts. with SCAD has not been shown yet. PURPOSE: To assess the influence of estimated glomerular filtration rate (eGFR) on the prognostic role of PTH and other MM markers in pts. with SCAD. METHODS: We analyzed the prognostic value of MM markers (PTH, klotho, phosphate, calcidiol [25-hydroxyvitamin D], and fibroblast growth factor-23 [FGF23]) in 964 pts. with SCAD and eGFR<60ml/min/1.73 m2 (LGFR) vs pts. with eGFR≥60ml/min/1.73 m2 (HGFR) included in five hospitals of Madrid. The main outcome was the combination of death with ischemic events (any acute coronary syndrome, ischemic stroke or transient ischemic attack). eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). RESULTS: Age was 60.0 (52.0-72.0) years, 76.2% of patients were men, and eGFR was 80.4 (65.3-93.1) ml/min/1,73 m2. Median follow-up was 5.39 (2.81-6.92) years. There were 790 pts. with HGFR and 174 with LGFR. In HGFR pts., predictors of ischemic events or death were plasma levels of calcidiol [HR=0.023 (0.94-0.99) p=0.023], FGF23 [HR=1.00 (1.00-1.003) p=0.036], non-HDL cholesterol [HR=1.01 (1.00-1.01) p=0.026] and high sensitivity troponin I [HR=5.12 (1.67-15.59) p=0.004], along with age [HR=1.03 (1.01-1.05) p=0.01], treatment with statins [HR=0.36 (0.19-0.68) p=0.002], nitrates [HR=1.13 (1.07-2.79) p=0.027], dihydropyridines [HR=1.71 (1.05-2.77) p=0.032], verapamil [HR=5.71 (1.35-24.1) p=0.018], and proton-pump inhibitors [HR=2.23 (1.36-3.68) p= 0.002]. In the LGFR subgroup, predictors of death or ischemic events were PTH plasma levels, [HR=1.01 (1.00-1.01) p=0.005], eGFR [HR=0.96 (0.94-0.99) p=0.004], age [HR=1.06 (1.02-1.10) p=0.003], caucasian race [HR=0.04 (0.004-0.380) p=0.005], and treatment with insulin [HR=2.6 (1.20-5.63) p=0.015]. CONCLUSIONS: In pts. with SCAD, PTH is an independent predictor of poor outcomes only in those with eGFR<60ml/min/1.73 m2, while in pts. with eGFR≥60ml/min/1.73 m2 calcidiol and FGF23 become the only components of MM that may predict prognosis. Then, renal function influences the predictive power of MM markers in pts. with SCAD.
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Doença da Artéria Coronariana , Insuficiência Renal Crônica , Idoso , Taxa de Filtração Glomerular , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Minerais , Prognóstico , Insuficiência Renal Crônica/complicaçõesRESUMO
Background. Mineral metabolism (MM) system and N-terminal pro-brain natriuretic peptide (NT-ProBNP) have been shown to add prognostic value in patients with stable coronary artery disease (SCAD). However, the influence of NT-ProBNP on the prognostic role of MM in patients with SCAD has not been shown yet. The objective of this study is to assess the influence of NT-ProBNP on the prognostic role of MM markers in patients with SCAD. Methods: We analyzed the prognostic value of MM markers (parathormone (PTH), klotho, phosphate, calcidiol (25-hydroxyvitamin D3), and fibroblast growth factor-23) in 964 patients with SCAD and NT-ProBNP > 125 pg/mL vs. patient with NT-ProBNP ≤ 125 pg/mL included in five hospitals in Spain. The main outcome was the combination of death, heart failure, and ischemic events (any acute coronary syndrome, ischemic stroke, or transient ischemic attack). Results: A total of 622 patients had NT-proBNP > 125 pg/mL and 342 patients had NT-ProBNP ≤ 125 pg/mL. The median follow-up was 5.1 years. In the group of NT-proBNP > 125 pg/mL, the patients were older, and there were more females and smokers than in the group of patients with normal NT-proBNP. Additionally, the proportion of patients with hypertension, atrial fibrillation, ejection fraction < 40%, cerebrovascular attack, or prior coronary artery bypass graft was higher in the high NT-proBNP group. In the high NT-proBNP patients, the predictors of poor prognosis were PTH (HR = 1.06 (1.01−1.10), p < 0.001) and NT-proBNP (HR = 1.02 (1.01−1.03), p = 0.011), along with age (HR = 1.039 (1.02−1.06), p < 0.001), prior coronary artery bypass graft (HR = 1.624 (1.02−2.59), p = 0.041), treatment with statins (HR = 0.32 (0.19−0.53), p < 0.001), insulin (HR = 2.49 (1.59−4.09), p < 0.001), angiotensin receptor blockers (HR = 1.73 (1.16−2.56), p = 0.007), nitrates (HR = 1.65 (1.10−2.45), p = 0.014), and proton pump inhibitors (HR = 2.75 (1.74−4.36), p < 0.001). In the NT-proBNP ≤ 125 pg/mL subgroup, poor prognosis predictors were plasma levels of non-high-density lipoprotein (non-HDL) cholesterol (HR = 1.01 (1.00−1.02), p = 0.014) and calcidiol (HR = 0.96 (0.92−0.99), p = 0.045), as well as treatment with verapamil (HR = 11.28 (2.54−50.00), p = 0.001), and dihydropyridines (HR = 3.16 (1.63−6.13), p = 0.001). Conclusion: In patients with SCAD and NT-ProBNP > 125 pg/mL, PTH and NT-ProBNP, which are markers related to ventricular damage, are predictors of poor outcome. In the subgroup of patients with NT-ProBNP ≤ 125 pgm/L, calcidiol and non-HDL cholesterol, which are more related to vascular damage, are the independent predictors of poor outcome. Then, in patients with SCAD, baseline NT-ProBNP may influence the type of biomarker that is effective in risk prediction.
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BACKGROUND: In chronic kidney disease (CKD) patients, the ability to excrete a phosphate load is impaired. Compensatory increase in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) promote phosphaturia. Serum FGF23 concentration is considered an early biomarker of excess phosphate load and high levels of FGF23 have been associated with increased mortality. In the present study, we have evaluated the changes in plasma FGF23 after treatment with the phosphate binder lanthanum carbonate in patients with CKD-3 and a normal serum phosphate concentration. METHODS: Eighteen Caucasian CKD Stage 3a/3b patients with serum phosphate <4.5 mg/dL were recruited in a prospective longitudinal open-label study. Patients received a 4-week period of standardized phosphorus-restricted diet containing 0.8 g/Kg/day protein. Thereafter, the same diet was maintained and patients received lanthanum carbonate (750 mg with the three main meals) for 4 weeks. RESULTS: No significant changes were observed in serum phosphate, however, lanthanum carbonate significantly decreased urinary excretion of phosphate and fractional excretion of phosphate (P < 0.004). This was accompanied by a significant decrease in carboxyterminal FGF23 (median percent change from baseline -21.8% (interquartile range -4.5, -30%), P = 0.025). No changes were observed in PTH. CONCLUSIONS: In conclusion, lanthanum carbonate reduced phosphate load, as assessed by urinary phosphate excretion, and also reduced plasma FGF23 in CKD-3 patients. This occurs in the presence of unchanged normal serum phosphate levels.
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Fatores de Crescimento de Fibroblastos/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/tratamento farmacológico , Lantânio/farmacologia , Fósforo/metabolismo , Idoso , Feminino , Fator de Crescimento de Fibroblastos 23 , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/patologia , Estudos Longitudinais , Masculino , Prognóstico , Estudos ProspectivosRESUMO
Objectives: The contribution of the clinical laboratory to diagnostics is increasingly important since a great deal of clinical decisions rely on laboratory test results. Content: Parathyroid hormone (PTH) measurement presents a considerable analytical variability due to the heterogeneity of its circulating forms and the antigenic configuration of the different assays commercially available. Such variability may have an impact on pathological conditions associated with significant increases in circulating PTH, as it is the case of chronic kidney disease (CKD). Summary: Despite the recent identification of new molecules involved in bone and mineral disorders associated with CKD, such as klotho or the fibroblastic factor 23 (FGF23), nephrologists still base their clinical decisions on PTH concentrations. The problem is that unawareness of these analytical considerations may cause errors in the clinical interpretation of test results. Outlook: This systematic review addresses these issues from the clinical laboratory perspective and proposes new approaches related to PTH method selection and result expression. These new strategies will help laboratory medicine specialists and nephrologist better determine the status of CKD patients.
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Twenty years have passed since the identification of klotho and the fibroblast growth factor 23 (FGF23), the regulatory binomial of phosphate homeostasis. Being kidney the main source of klotho as well as a target organ in the phosphate regulation, most studies involving klotho and FGF23 had a "nephrocentric" focus. Considering that circulating FGF23 can reach exaggerated levels at the end stage of chronic kidney disease (CKD), the bias of this approach allowed to recognize the harmful "off target" klotho-independent effect of FGF23. All of these findings have caused a revolution on our previous knowledge about mineral homeostasis and currently, we are facing a new scenario in the clinical management of CKD, where FGF23 emerges simultaneously as an early biomarker of phosphate retention but also as a therapeutic target. In this review, we describe the disturbances of FGF23 in the CKD and we focus on how the maintenance of circulating FGF23 into a supraphysiological adaptive range from the initial stages of CKD and the control of "unlimited hyperphosphatonism" generated by the resistance to FGF23 action at end stages should emerge as new treatment paradigms in CKD-MBD. The recent development of an automated FGF23 assay, already validated for clinical use, should be the starting point to individualize all our knowledge from epidemiological studies and will allow us to use it properly for the patient's personalized care. Then, now we are in the momentum to assess the discriminating thresholds to distinguish the physiological adaptive FGF23 elevation related to each CKD stage from the exaggerated increase that would be interpreted as a poor regulatory compensation that will requires the adoption of therapeutic intervention.
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Nefrologia , Insuficiência Renal Crônica , Biomarcadores , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Glucuronidase , Humanos , Proteínas Klotho , Fosfatos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapiaRESUMO
Twenty years have passed since the identification of klotho and the fibroblast growth factor 23 (FGF23), the regulatory binomial of phosphate homeostasis. Being kidney the main source of klotho as well as a target organ in the phosphate regulation, most studies involving klotho and FGF23 had a «nephrocentric¼ focus. Considering that circulating FGF23 can reach exaggerated levels at the end stage of chronic kidney disease (CKD), the bias of this approach allowed to recognize the harmful «off target¼ klotho-independent effect of FGF23. All of these findings have caused a revolution on our previous knowledge about mineral homeostasis and currently, we are facing a new scenario in the clinical management of CKD, where FGF23 emerges simultaneously as an early biomarker of phosphate retention but also as a therapeutic target. In this review, we describe the disturbances of FGF23 in the CKD and we focus on how the maintenance of circulating FGF23 into a supraphysiological adaptive range from the initial stages of CKD and the control of «unlimited hyperphosphatonism¼ generated by the resistance to FGF23 action at end stages should emerge as new treatment paradigms in chronic kidney disease - mineral and bone disorders (CKD-MBD). The recent development of an automated FGF23 assay, already validated for clinical use, should be the starting point to individualize all our knowledge from epidemiological studies and will allow us to use it properly for the patient's personalized care. Then, now we are in the momentum to assess the discriminating thresholds to distinguish the physiological adaptive FGF23 elevation related to each CKD stage from the exaggerated increase that would be interpreted as a poor regulatory compensation that will requires the adoption of therapeutic intervention.
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Fator de Crescimento de Fibroblastos 23/fisiologia , Insuficiência Renal Crônica/etiologia , Humanos , Nefrologia , Medicina de PrecisãoRESUMO
It is essential to study the factors associated with the evolution of aortic stenosis progression (ASP) to develop therapies that could reduce it. We studied 283 patients 6 months after acute coronary syndrome (ACS). ASP was defined as an increase in the maximum aortic velocity of at least 0.5 m/s between the echocardiogram performed during ACS hospitalization and the last one recorded in the electronic medical registry. The median follow-up was 72.4 months. Twenty patients (7%) had ASP. A multivariate binary logistic regression analysis was performed showing that PCSK9 plasma levels (OR, 0.668 CI (0.457-0.977); p = 0.038), HS-CRP (OR, 1.034 CI (1.005-1.063); p = 0.022), the presence of dyslipidemia (OR, 4.622 CI (1.285-16.618); p = 0.019), the history of PAD (OR, 9.453 CI (1.703-52.452); p = 0.010), and GFR (OR, 0.962 CI (0.939-0.986); p = 0.002) were independent predicting factors of ASP. In patients with ischemic heart disease, low plasma levels of PCSK9 and elevated levels of HS-CRP are independent predictors of ASP.
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Estenose da Valva Aórtica/sangue , Proteína C-Reativa/análise , Doença da Artéria Coronariana/sangue , Pró-Proteína Convertase 9/sangue , Idoso , Estenose da Valva Aórtica/diagnóstico por imagem , Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico , Progressão da Doença , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
AIMS: There are controversial data on the ability of the components of mineral metabolism (vitamin D, phosphate, parathormone [PTH], fibroblast growth factor-23 [FGF23], and klotho) to predict cardiovascular events. In addition, it is unknown whether they add any prognostic value to other well-known biomarkers. METHODS AND RESULTS: In 969 stable coronary patients, we determined plasma levels of all the aforementioned components of mineral metabolism with a complete set of clinical and biochemical variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hs-TnI), and high-sensitivity C-reactive protein. Secondary outcomes were ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and heart failure or death. The primary outcome was a composite of the secondary outcomes. Median follow-up was 5.39 years. Age was 60 (52-72) years. Median glomerular filtration rate was 80.4 (65.3-93.1) mL/min/1.73 m2 . One-hundred and eighty-five patients developed the primary outcome. FGF23, PTH, hs-TnI, and NT-proBNP were directly related with the primary outcome on univariate Cox analysis, while Klotho and calcidiol were inversely related. On multivariate analysis, only PTH (HR 1.058 [CI 1.021-1.097]; P = 0.002) and NT-proBNP (HR 1.020 [CI 1.012-1.028]; P < 0.001) were independent predictors of the primary outcome but also for the secondary outcome of heart failure or death (HR 1.066 [CI 1.016-1.119]; P = 0.009 and HR 1.024 [CI 1.014-1.034]; P < 0.001, respectively). PTH was the only biomarker that predicted ischaemic events (HR 1.052 [1.010-1.096]; P = 0.016). Patients were divided in two subgroups according to FGF23 plasma levels. PTH retained its prognostic value only in patients with FGF23 levels above the median (>85.5 RU/mL) (P < 0.001) but not in patients with low FGF23 levels (P = 0.551). There was a significant interaction between FGF23 and PTH (P = 0.002). However, there was no significant interaction between PTH and both klotho and calcidiol levels. CONCLUSIONS: Parathormone is an independent predictor of cardiovascular events in coronary patients, adding complimentary prognostic information to NT-proBNP plasma levels. This predictive value is restricted to patients with high FGF23 plasma levels. This should be considered in the design of future studies in this field.
Assuntos
Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Idoso , Fator de Crescimento de Fibroblastos 23 , Humanos , Pessoa de Meia-Idade , Hormônio Paratireóideo , PrognósticoRESUMO
Our purpose was to assess a possible association of inflammatory, lipid and mineral metabolism biomarkers with coronary artery ectasia (CAE) and to determine a possible association of this with acute atherotrombotic events (AAT). We studied 270 patients who underwent coronary angiography during an acute coronary syndrome 6 months before. Plasma levels of several biomarkers were assessed, and patients were followed during a median of 5.35 (3.88-6.65) years. Two interventional cardiologists reviewed the coronary angiograms, diagnosing CAE according to previously published criteria in 23 patients (8.5%). Multivariate binary logistic regression analysis was used to search for independent predictors of CAE. Multivariate analysis revealed that, aside from gender and a diagnosis of dyslipidemia, only monocyte chemoattractant protein-1 (MCP-1) (OR = 2.25, 95%CI = (1.35-3.76) for each increase of 100 pg/mL, p = 0.001) was independent predictor of CAE, whereas mineral metabolism markers or proprotein convertase subtilisin/kexin type 9 were not. Moreover, CAE was a strong predictor of AAT during follow-up after adjustment for other clinically relevant variables (HR = 2.67, 95%CI = (1.22-5.82), p = 0.013). This is the first report showing that MCP-1 is an independent predictor of CAE, suggesting that CAE and coronary artery disease may share pathogenic mechanisms. Furthermore, CAE was associated with an increased incidence of AAT.
RESUMO
Background: The prevalence of low- turnover bone disease (LTBD) in peritoneal dialysis (PD) patients is higher than in hemodialysis (HD) patients. LTBD patients may be at risk for vascular calcification, and cardiovascular disease. Current therapy for chronic kidney disease metabolic bone disorders (CKD-MBD) is guided by biochemical parameters, as bone biopsy is not used in routine clinical care. Methods: We assessed intact PTH (iPTH: 1-84PTH plus non-1-84PTH), 1-84PTH, and the 1-84PTH/non-1-84PTH ratio in 129 hemodialysis and 73 PD prevalent patients dialyzed with solutions containing 1.75 mmol/L calcium. Results: Hemodialysis and PD patients presented similar iPTH and tCa values and prevalence of putative LTBD as defined according to KDOQI iPTH cut-off levels or 1-84 PTH levels. However, iCa accounted for a higher percentage of tCa in PD (53%) than in hemodialysis (39%) p < 0.001, and the 1-84PTH/non-1-84PTH ratio was lower in PD than in hemodialysis patients (0.44 ± 0.12) vs. (0.60 ± 0.10), p < 0.001. The prevalence of putative LTBD when using the coexistence of 1-84PTH/non-1-84PTH ratio < 1.0 and iPTH < 420 pg/m, was higher in PD than in hemodialysis patients (73 vs. 16% respectively, p < 0.001). In a multivariate logistic regression analysis, dialysis modality was the main determinant of the 1-84PTH/non-1-84PTH ratio. Conclusion: Solutions containing 1.75 mmol/L calciums are associated to a higher proportion of non-1-84PTH fragments in PD than in HD patients. Different analytical criteria result in widely different estimates of LTBD prevalence, thus impairing the ability of clinicians to optimize therapy for CKD-MBD.
RESUMO
Parathormone plays a key role in controlling mineral metabolism. PTH is considered a uremic toxin causing cardiovascular damage and cardiovascular mortality in dialysis patients. There are two different assays to measure PTH called 2nd generation or intact PTH (iPTH) and 3rd generation or bioPTH (PTHbio). OBJECTIVE: To evaluate the differences in mortality of dialysis patients between both assays to measure PTH, as well as the possible prognostic role of the PTHbio/iPTH ratio. METHODS: 145 haemodialysis patients were included with 2-year monitoring including baseline laboratory test and annually thereafter. RESULTS: 21 patients died in the first year and 28 in the second. No correlation was found between PTH, PTHbio and PTHbio/iPTH ratio with mortality. Both PTH have a perfect correlation between them and correlate similarly with other molecules of the mineral metabolism. The extreme baseline values of PTH are those of higher mortality. In survival by iPTH intervals (according to guidelines and COSMOS study), a J curve is observed. When iPTH increases, the ratio decreases, possibly when increasing fragments no. 1-84. There is no greater prognostic approximation on mortality with PTHbio than PTHi. There was also no difference in mortality when progression ratio PTHbio/PTHi was analysed. CONCLUSIONS: We didn't find any advantages to using bioPTH vs. PTHi as a marker of mortality. BioPTH limits of normality must be reevaluated because its relationship with iPTH is not consistent. Not knowing these limits affects its prognostic value.