Aims
High serum phosphate is linked to cardiovascular morbidity and mortality in the general population. Fibroblast growth factor 23 (FGF-23) is a critical phosphate regulating hormone, potentially ...reflecting phosphate load better than a single serum phosphate measurement. Recent pioneering echocardiographic studies associated FGF-23 with left-ventricular morphology. However, the association between FGF-23 and left-ventricular function is unknown, prompting us to investigate this relationship in our HOM SWEET HOMe study.
Methods and results
We studied the association between C-terminal FGF-23, coronary artery disease, and left-ventricular function in 885 subjects undergoing elective coronary angiography. Left-ventricular function was assessed with ventriculography. More, pro-brain natriuretic peptide (pro-BNP) plasma levels were measured. The presence of left-ventricular hypertrophy and atrial fibrillation was assessed by electrocardiography. Patients with an ejection fraction <40% had significantly higher FGF-23 levels compared with patients with the ejection fraction >40% (P< 0.001). In multivariable regression analysis, the observed relationship between FGF-23 and left-ventricular function remained significant after adjustment for estimated glomerular filtration rate, presence of left-ventricular hypertrophy, and other confounding variables. In accordance, FGF-23 significantly correlated with pro-BNP plasma levels (r = 0.31; P< 0.001). Prevalent atrial fibrillation was associated with elevated FGF-23 levels, while the presence of coronary artery disease was not.
Conclusions
Fibroblast growth factor 23 levels are associated with left-ventricular function and atrial fibrillation even in the absence of renal function impairment. Of note, these cross-sectional data cannot prove causality; therefore, future studies will have to discern whether FGF-23 exerts a direct untoward effect on the myocardium, or rather represents an 'innocent bystander' which reflects a high phosphate burden.
Monocytes are key components of the innate immune system and are circulating precursors of tissue macrophages. Phenotypically and functionally, monocytes are a heterogeneous leukocyte subset. Based ...on the expression of CD14 and CD16, three human monocyte subsets can be distinguished: CD14++CD16−, CD14++CD16+ and CD14(+)CD16+ monocytes. The latter two subsets are often summarized as CD16+ monocytes. As these CD16+ cells are expanded in inflammatory conditions including end-stage renal disease, they have traditionally been termed proinflammatory monocytes, which is in contrast to murine monocyte nomenclature. More, each dialysis session induces a transient CD16+ monocytopenia.. In end-stage renal disease, both higher predialytic counts of CD16+ monocytes, and dialysis-induced CD16+ monocyte kinetic are predictors of cardiovascular outcome. So far, the functional differences of monocyte subsets and their pathophysiological role are still insufficiently understood.
Les monocytes circulants représentent 5 à 10 % des leucocytes. Ils sont issus de cellules myéloïdes de la moelle osseuse ; mais ils sont caractérisés par une grande variété phénotypique et fonctionnelle. Ils expriment à leur surface des antigènes CD14 et CD16. Selon l’intensité de l’expression de ces antigènes, plusieurs catégories de monocytes ont été distinguées. Les monocytes jouent un rôle pivot dans l’immunité innée et acquise. Ils sont même vus par certains comme des précurseurs des macrophages tissulaires et des cellules dendritiques. Ceux qui expriment le CD16 (dénommé CD16+ monocytes), sont classiquement considérés comme pro-inflammatoires, y compris chez l’insuffisant rénal chronique. Le taux de CD16+ augmente de façon importante au début de la séance d’hémodialyse et redevient normal à la fin de celle-ci. Cela peut positionner les monocytes comme des marqueurs de biocompatibilité. Les monocytes CD14++CD16+ sont des marqueurs indépendants du risque cardiovasculaire chez l’hémodialysé. Comme chez le sujet à fonction rénale normale, les CD16+ sont corrélés à l’épaisseur intima-média chez le transplanté rénal, à la présence d’une maladie cardiovasculaire et d’une insulinorésistance. En cas de syndrome métabolique, ils pourraient donc être le témoin des perturbations endocriniennes et vasculaires qui surviennent à l’échelon cellulaire. Devant toutes ces constatations, il semble intéressant de développer des recherches sur les fonctions des différentes catégories de monocytes.
Abstract
Background and Aims
In dialysis patients, cholesterol-lowering therapy with statins is less effective than in other high-risk patients. This may partly be explained by a shift from ...cholesterol synthesis, which is inhibited by statin treatment, towards cholesterol absorption, which is inhibited by ezetimibe. In line, markers of cholesterol absorption – such as campesterol - better predict atherosclerotic cardiovascular events than markers of cholesterol synthesis – such as lathosterol - in dialysis patients. We now investigated in our CARE FOR HOMe study whether a similar shift towards cholesterol absorption occurs in non-dialysis chronic kidney disease (CKD), and whether the campesterol / lathosterol ratio predicts outcome in non-dialysis CKD patients.
Method
Since 2008, 599 participants suffering from chronic kidney disease have been included into the CARE FOR HOME study, an observational cohort study. 555 patients had baseline samples available for analyses of the lathosterol / cholesterol ratio as a marker for cholesterol synthesis, and the campesterol / cholesterol ratio as a marker for cholesterol absorption. We excluded those participants who were currently treated with statins or other lipid lowering drugs, leaving 251 patients for this analysis. Participants were followed annually for major atherosclerotic cardiovascular events (MACE), defined as non-fatal acute myocardial infarction, non-fatal ischemic stroke, cerebrovascular / peripheral arterial or coronary revascularization, major amputation above the ankle and cardiovascular death. Additionally, all-cause death and the composite endpoint MACE and all-cause death were explored. We performed univariate (Model 1) and multivariate Cox regression analysis, adjusting for age, gender (Model 2), estimated glomerular filtration rate (eGFR), log-transformed albuminuria (Model 3), prevalent cardiovascular disease, current smoking, diabetes mellitus, systolic blood pressure and body mass index (Model 4). The primary hypothesis was that patients with a high campesterol / lathosterol ratio had a higher event rate.
Results
Neither lathosterol / cholesterol ratio (r = 0.022, p = 0.730), nor campesterol / cholesterol ratio (r = 0.042; p = 0.519) nor the campesterol / lathosterol ratio (r = -0.103; p = 0.105) correlated significantly with eGFR. During follow-up of 5.1 ± 2.1 years, 47 participants suffered from MACE, 46 participants died and 61 participants reached the composite endpoint of MACE or all-cause death. In univariate Cox regression analysis, campesterol / lathosterol ratio did not significantly predict atherosclerotic cardiovascular events (HR 0.740; 0.368 – 1.487), all-cause death (HR 0.564; 0.277 – 1.145) or the composite endpoint (HR 0.652; 0.355 – 1.196). After full adjustment, results were not different: Campesterol / lathosterol ratio was not significantly associated with all three endpoints: MACE (HR 1.064; 0.507 – 2.231), all-cause death (HR 0.818; 0.420 – 1.594) and MACE and all-cause death (HR 0.956; 0.525 – 1.744).
Conclusion
We did not observe a shift from cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD. Campesterol / lathosterol ratio did not predict future MACE or all-cause death in non-dialysis CKD. These findings do not support the concept that CKD patients may preferentially benefit from ezetimibe rather than from statin treatment.
To the Editor:
Pergola et al. (July 28 issue)
1
describe the beneficial effect of the new synthetic triterpenoid, bardoxolone methyl, on the glomerular filtration rate (GFR) in patients with diabetes ...and chronic kidney disease (CKD). The main mechanism of action of bardoxolone is the activation of Nrf2, a ubiquitous transcription factor involved in the up-regulation of many cytoprotective genes with consecutive antiinflammatory effects, inhibition of nuclear factor κB (NF-κB), and decreased oxidative stress.
Importantly and without explanation, hypomagnesemia developed in a dose-dependent manner in 26% of bardoxolone-treated patients as compared with 5% of patients in the placebo group. Mounting evidence . . .
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