Cardiovascular Events In Chronic Kidney Disease Patients Research Articles

FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment

High levels of the phosphaturic hormone fibroblast growth factor 23 (FGF-23) predict mortality in haemodialysis patients. The prognostic relevance of increased plasma FGF-23 levels in patients with less advanced chronic kidney disease (CKD) who are not on dialysis therapy is presently unknown. We measured plasma c-terminal FGF-23 levels in 149 CKD patients not undergoing dialysis treatment. Patients were stratified by their baseline FGF-23 levels (>104 vs ≤ 104 rU/mL) and followed for a period of 4.8 ± 0.9 years. During the follow-up, the pre-specified combined clinical endpoint was the first occurrence of a cardiovascular event, e.g. myocardial infarction, coronary artery angioplasty/stenting/bypass surgery, stroke, carotid endarterectomy/stenting, non-traumatic lower extremity amputation, lower limb artery surgery/angioplasty/stenting or death. At baseline, elevated FGF-23 levels >104 rU/mL were associated with more advanced CKD. Traditional cardiovascular risk factors and prevalent cardiovascular disease did not differ between CKD patients with high vs low FGF-23 levels. Fifty patients experienced a cardiovascular event during follow-up. Compared with CKD patients with FGF-23 ≤104 rU/mL, CKD patients with FGF-23 levels above the cut-off had worse event-free survival at univariate (log-rank test P = 0.012) and multivariate analysis [hazard ratio 2.49 (95% CI 1.40-4.39); P = 0.002]. Elevated FGF-23 plasma levels predict cardiovascular events in CKD patients not on dialysis therapy. This finding complements two recent cohort studies in which incident and prevalent haemodialysis patients with highest FGF-23 levels had worst survival. Lowering FGF-23 levels (e.g. by oral phosphate binder medication) could emerge as a promising new therapeutic option to reduce cardiovascular morbidity in CKD patients.

A Systolic Parameter Defined as the Ratio of Brachial Pre-Ejection Period to Brachial Ejection Time Predicts Cardiovascular Events in Patients With Chronic Kidney Disease

Patients with chronic kidney disease (CKD) are associated with an increased risk of cardiovascular (CV) events. An increase in the ratio of the pre-ejection period (PEP) to ejection time (ET) is correlated with a decrease of left ventricular systolic function. Brachial PEP (bPEP) and brachial ET (bET) can be automatically determined from an ankle-brachial index (ABI)-form device. The aim of this study is to investigate whether bPEP/bET is a useful predictor for CV events in patients with CKD. We consecutively enrolled 242 CKD patients from our outpatient department of internal medicine. The bPEP and bET were measured using an ABI-form device. CV events were defined as cardiac death, stroke, myocardial infarction, and hospitalization for congestive heart failure. The study subjects were followed until the first episode of CV events occurred. The relative CV event risk was analyzed by Cox-regression methods. In the multivariate analysis, the presence of diabetes (hazard ratio (HR), 3.531; P=0.014), increased bPEP/bET (HR, 1.054; P=0.026), and decreased serum albumin level (HR, 0.525; P=0.005) were independent predictors for CV events. The study findings show that bPEP/bET is a useful predictor of CV events in CKD patients. Screening CKD patients by means of bPEP/bET might help to identify patients at high risk of increased CV events.

Sevelamer versus calcium-based phosphate binders in chronic kidney disease: what should we conclude from the evidence to date?

Calcium-based phosphate binders have traditionally been considered standard first-line treatment for control of hyperphosphataemia in chronic kidney disease (CKD). However, several cross-sectional studies have observed that prescribed calcium intake from phosphate binders is dose-dependently associated with the degree of vascular calcification in CKD patients [1,2]. Other studies have demonstrated an association between vascular calcification scores and an increased risk of cardiovascular disease [3– 5]. Although there is presently no proof that interventions that reduce the surrogate outcome of vascular calcification lead to reduced cardiovascular events in CKD patients, the K/DOQI guidelines have recommended that the ‘total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1500 mg/day (opinion), and the total intake of elemental calcium (including dietary calcium) should not exceed 2000 mg/day (opinion)’ [6]. If these guidelines are followed, there is likely to be a substantial shift in clinical practice away from the use of calciumbased phosphate binders to non-calcium-based phosphate binders, such as sevelamer, which are considerably more expensive. This raises the important question of just how good is the evidence that sevelamer therapy results in superior patient-level outcomes (i.e. ‘hard’ clinical end-points) compared with calcium-based phosphate binder therapy? To date, there has only been one randomized controlled trial (RCT) of sevelamer versus calcium-based binders, which has been adequately powered for mortality. The Dialysis Clinical Outcomes Revisited (DCOR) study involved 75 centres and 2103 haemodialysis patients randomly allocated to receive either sevelamer or a calcium-based phosphate binder for a mean follow-up period of ∼20 months [7]. Sevelamer-treated patients experienced comparable allcause mortality [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.79–1.10] and cardiovascular mortality (HR 0.93, 95% CI 0.74–1.17) to patients receiving calciumbased binders. Based on a significant interaction between the pre-specified variable of age and treatment effect (P = 0.02), a subsequent age-stratified analysis demonstrated that sevelamer was associated with a reduction in mortality in patients aged 65 years or older (HR 0.77, 0.61– 0.96). However, these results were limited by the fact that the authors did not correct their interaction assessments for multiple comparisons, which would have yielded a nonsignificant result. A subsequent intention-to-treat analysis of the DCOR study using pre-planned secondary analyses and Centers for Medicare & Medicaid Services data demonstrated no significant differences in overall or cardiovascular mortality and no significant interaction between age and treatment effect [8]. A meta-analysis of RCTs, including the DCOR study, observed that sevelamer treatment was associated with similar all-cause mortality (risk difference −2%, 95% CI −6%– 2%; 5 RCTs and 2429 participants) and cardiovascular mortality (risk difference −1%, 95% CI −4%–2%; 3 RCTs and 2102 participants) compared with calcium-based phosphate binder therapy [9]. The authors concluded that there was ‘no convincing evidence that sevelamer improves clinically relevant outcomes in ESRD patients’ and that ‘recommendations for the routine use of sevelamer in dialysis patients are not supported by current data.’ In this issue of Nephrology Dialysis and Transplantation, Jamal et al. report the results of an updated systematic review of the effects of calcium-based versus non-calciumbased phosphate binders on mortality in CKD patients [10]. Eight RCTs of sevelamer versus calcium-based binders were selected. The study was sponsored by Genzyme (manufacturers of sevelamer) and one of the authors declared a potential conflict of interest with Genzyme. Similar to the findings of the previous meta-analysis, Jamal et al. reported no significant differences between patients treated with sevelamer or calcium-based phosphate binders with respect to coronary artery calcification (WMD −76.35, 95% CI −158.25–5.55; 5 RCTs and 469 participants), cardiovascular events [relative risk (RR) 0.85, 95% CI 0.35– 2.03; two RCTs and 153 participants] or all-cause mortality (RR 0.68, 95% CI 0.41–1.11; eight RCTs and 2873 participants). In spite of the non-significant differences between the groups, the authors concluded that there were ‘trends’ towards decreased all-cause mortality, cardiovascular mortality and coronary artery calcification associated with noncalcium-based phosphate binders and that future studies are needed to conduct ‘research on the mechanism by which non-calcium-based phosphate binders reduce mortality or

Key insights into present and future treatments of anaemia in CKD patients

Key insights into present and future treatments of anaemia in CKD patients

Abstract 967: Parathyroidectomy Reduces Cardiovascular Events And All-cause Mortality In Renal Hyperparathyroidism

Background: Secondary hyperparathyroidism (SHPT) and its associated abnormalities in mineral metabolism increase the risk of cardiovascular morbidity and death in chronic kidney disease (CKD). The effect of parathyroidectomy (PTX) on the incidence of major cardiovascular events in CKD patients with SHPT is unknown. We tested the hypothesis that PTX reduces the incidence of cardiovascular complications and death in CKD patients with severe SHPT scheduled for PTX, comparing the outcome of patients treated or not treated by surgery. Methods: The study comprised 118 CKD patients with SHPT on maintenance hemodialysis, unresponsive to medical treatment, and scheduled for PTX. Patients underwent comprehensive cardiovascular evaluations at baseline. They were followed up until death, occurrence of major cardiovascular events, or kidney transplantation. Results: No deaths related to surgery occurred. After a median follow-up of 30 months, 50 patients (42.4%) had undergone PTX while 68 (57.9%) had not. The groups were comparable in terms of age, sex, race, parathyroid hormone (PTH), calcium, phosphate, calcium x phosphate product, and all major cardiovascular variables, except diastolic blood pressure. PTX was associated with a reduced incidence of major cardiovascular events (log-rank= 0.02) and overall mortality (log-rank= 0.001). Cox proportional multivariate analysis showed that variables significantly and independently associated with events were PTX (RR=2.36, CI 1.11–6.32, p=0.02) and age (RR=1.07, IC 1.02–1.14, p=0.009). All-cause mortality was related to PTX (RR=2.34, CI 1.25–5.14, p=0.007) and hematocrit (RR=1.15, CI 1.03–1.29, p=0.01). Conclusion: PTX confers protection against future major cardiovascular events and death in select CKD patients with severe refractory SHPT.

Cardiovascular remodelling and extracellular fluid excess in early stages of chronic kidney disease

Patients with a mild to moderate decrease of glomerular filtration rate (GFR) are at risk of cardiovascular (CV) events and CV remodelling has been demonstrated in patients with advanced chronic kidney disease (CKD). However, early stages of CKD and the mechanisms involved in these modifications have not been studied. A total of 104 patients with early CKD (mean GFR 60+/-21 ml/min/1.73 m(2)) had cardiac and vascular ultrasound study and measurement of extracellular fluid by multifrequence spectroscopic bioimpedance. GFR decline was associated with left ventricular (LV) remodelling or hypertrophy in 58 and 68% of DOQI-2 and DOQI-3 patients, respectively and impaired LV diastolic function. GFR decrease was also associated with common carotid remodelling and increased aorta stiffness. Cardiac and vascular remodelling were significantly associated with an excess of extracellular fluid (ECFe) evidenced as early as DOQI-2 stage. In multivariate analysis with adjustment for GFR, ECFe, age and systolic blood pressure (sBP), GFR was no longer independently associated with cardiac and vascular remodelling, whereas ECFe was an independent determinant of LV hypertrophy, left atrium enlargement, common carotid diameter and intima media thickness. This study shows that CV remodelling and ECF excess occurred at a very early stage of CKD. The independent association between ECF excess and cardiac and vascular remodelling and hypertrophy may be instrumental in the increased cardiovascular risk in CKD patients. Early therapeutic control of ECF may reduce CV events in CKD patients.

Matrix GLA Protein Gene Polymorphisms: Clinical Correlates and Cardiovascular Mortality in Chronic Kidney Disease Patients

Background: Increased vascular calcification plays an important role in the pathogenesis of cardiovascular events in chronic kidney disease (CKD) patients. It is the result of an active ossification process counteracted by ‘protective’ proteins, such as matrix GLA protein (MGP). Polymorphisms of MGP have been identified. Methods: The aim of this study was to define the distribution of two MGP polymorphisms (–7, –138) in 99 hemodialysis (HD) patients, in 26 patients with CKD stage 3 and in 135 age- and sex-matched healthy controls. Patients were followed up for 12 months to record any cardiovascular deaths. The cause of death was determined by medical doctors, considering the medical history of each patient. The primers were designed with Primer Express software. Results: MGP –138TT homozygotes were more frequent in the HD group versus controls (p = 0.0004). Additionally, the frequency of the T allele was significantly higher in the HD group (p = 0.0006). The frequency of the A allele of MGP-7 was significantly higher both in the HD group (p = 0.033) and in the CKD group (p = 0.0017) versus controls. MGP-7 GG homozygotes were significantly less common in the CKD group than in controls (p = 0.037). Combination –138TT –7AA was significantly more frequent in both CKD patients (p = 0.001) and in HD patients (p = 0.029) than in controls. Seventeen out of 99 HD patients experienced fatal cardiovascular events. Sixteen (94.1%) were –138TT homozygotes and either –7AA homozygotes or –7GA heterozygotes. Conclusion: This study suggests that CKD and HD patients have a different distribution of MGP gene polymorphism as compared with the normal population. Altered MGP gene polymorphism may be a negative prognostic factor for the progression to end-stage renal disease and for cardiovascular events in CKD patients.

Predictive cardiovascular risk factors in patients with chronic kidney disease (CKD)

Traditional cardiovascular risk factors and uremia-related specific factors have been identified in patients with CKD, explaining the highest risk for morbidity and mortality from cardiovascular disease. The aim of this study was to analyze the predictive power of several cardiovascular risk factors and markers in a population of stable patients with moderate CKD. One hundred twenty-eight (78 M, 50 F) outpatients with estimated glomerular filtration rate (GFR) <60 mL/min were included in the study. Medical records about cardiovascular factors were recorded. Analytical parameters and cardiac markers were analyzed. The patients were prospectively followed, and the end points were fatal and nonfatal cardiovascular events. After a mean follow-up of 22.3 months, 27 patients had a cardiovascular event. The patients who suffered a cardiovascular event were older (P= 0.002), with more anemia (P= 0.014), higher pulse pressure (P= 0.011), and cTnT levels (P= 0.000). In addition, they had more prevalence of LVH (P= 0.001), diabetes (P= 0.013), previous coronary heart disease (P= 0.008), chronic heart failure (P= 0.000), vascular peripheral disease (P= 0.006), and had also a higher score of 10-year coronary heart disease predicted risk (P= 0.006). Age [hazard ratio (HR) 1.07, P= 0.02], previous coronary artery disease (HR 4.08, P= 0.0012), and cTnT levels (HR 1.64, P= 0.0000) independently predicted cardiovascular events on multivariate Cox analysis. In stable patients with CKD, age and previous coronary artery disease were the traditional cardiovascular risk factors more predictive for cardiovascular events. Cardiac troponin T is a powerful marker of cardiovascular events in CKD patients.