Non-invasive imaging techniques and assessment of carotid vasa vasorum neovascularization: promises and pitfalls

Carotid adventitia vasa vasorum neovascularization (VVn) is associated with the initial stages of arteriosclerosis and with the formation of unstable plaque. However, techniques to accurately quantify that neovascularization in a standard, fast, non-invasive, and efficient way are still lacking. The development of such techniques holds the promise of enabling wide, inexpensive, and safe screening programs that could stratify patients and help in personalized preventive cardiovascular medicine. In this paper, we review the recent scientific literature pertaining to imaging techniques that could set the stage for the development of standard methods for quantitative assessment of atherosclerotic plaque and carotid VVn. We present and discuss the alternative imaging techniques being used in clinical practice and we review the computational developments that are contributing to speed up image analysis and interpretation. We conclude that one of the greatest upcoming challenges will be the use of machine learning techniques to develop automated methods that assist in the interpretation of images to stratify patients according to their risk

Carotid ultrasound for the early diagnosis of atherosclerosis in chronic kidney disease

Atherothrombotic disease (ATD) is a progressive disorder and its most common clinical manifestations, acute myocardial infarction and stroke, are responsible for the highest morbidity and mortality rates in the Western world. Sudden death due to infarction with no prior symptoms occurs in 50% of men and 64% of women.1 One of the main tools to control the incidence of vascular disease is prevention. Formulas are available to estimate cardiovascular risk (Framingham risk score, etc.)2 They are based on epidemiological studies that determine the risk of suffering a cardiovascular event (fatal or non-fatal) within 5 to 10 years.3 While the available system to calculate cardiovascular risk is easily generalisable, and universal, it does present some difficulties. The main drawback is its low sensitivity for detecting individuals at a high risk to suffer a cardiovascular event. Large epidemiological studies show that 62% of subjects with a prior history of myocardial infarction present none or only one of the cardiovascular risk factors,4 which, undoubtedly, prevents them from being properly identified at a time to take effective preventive actions. In recent years, there have been significant technological advances in medical imaging techniques, particularly in the field of vascular disease. Below, we describe the advantages, disadvantages and uses of imaging techniques in the general population and in chronic kidney disease (CKD) patients

Efecto inhibidor directo del incremento secuencial en las dosis de calcitriol intravenoso en el hiperparatiroidismo secundario severo. Evolución a largo plazo

Estudiamos en 10 pacientes en hemodiálisis con hiperparatiroidismo secundario severo (PTH > 50 pmol/L y calcio iónico > 4.4 mg/dl) el efecto inhibidor directo, sobre la función paratiroidea, de incrementos secuenciales de calcitriol intravenoso (2,4 y 6 μg post-hemodiálisis mantenidos 3,2 y 2, meses respectivamente). En segundo lugar analizamos el indice de fracaso terapéutico (necesidad de paratiroidectomía) después de 18 meses de seguimiento. Se utilizó un dializado de 2,5 mEq/l de calcio y como quelante del fósforo geles de hidróxido de aluminio para disminuir el riesgo de hipercalcemia. Valoramos la función paratiroidea después de los períodos de tratamiento con 2 y 6 μg mediante la construcción de la curva sigmoidal Ca-PTH. Consideramos que existía efecto inhibidor directo, no mediado por el calcio, cuando el descenso de los niveles de PTH intacta tras la máxima estimulación era superior al 20 % de sus valores antes del tratamiento. Cuatro pacientes respondieron a 2 μg. En 3 de los 6 pacientes no respondedores el producto Ca P no permitió incrementar la dosis. De los 3 pacientes restantes que alcanzaron la dosis de 6 μg se obtuvo respuesta en sólo 2. A los 18 meses de seguimiento el tratamiento con calcitriol intravenoso había fracasado en el 50 % de los pacientes y el resto continuaba tratamiento con dosis de mantenimiento inferiores a las iniciales. En conclusión, el tratamiento con calci triol intravenoso a dosis elevadas: 1) ejerce un efecto inhibidor directo dosis-dependiente sobre los niveles de PTH; 2) permite a largo plazo dosis de mantenimiento inferiores a las que indujeron la respuesta, lo que sugiere un efecto «sensibilizador» sobre las células paratiroideas, y 3) fracasa en un elevado porcentaje de pacientes (50 %) con hiperparatiroidismo secundario severo

Association of serum phosphorus with subclinical atherosclerosis in chronic kidney disease. Sex makes a difference

Abstract BACKGROUND: Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Serum phosphate has been associated to cardiovascular disease in the general population and this effect seems to be different according to sex. In the present study we analyze the effect of phosphate on subclinical atherosclerosis in the NEFRONA population and its effect depending on sex. DESIGN: Carotid ultrasound assessing the presence of plaques was performed by an itinerant team in 1687 CKD patients not in dialysis without previous cardiovascular events. Standard blood test and anthropometrical parameters were also recorded. RESULTS: Multivariate linear regression to model phosphate levels in patients with CKD showed an interaction of sex with age. Thus, among men, serum phosphate levels declined significantly with age almost linearly. Serum phosphate levels in women under the age of 40-45 years overlapped with those in men and then stayed above, showing and overall constant relationship. Multivariate logistic regression analysis showed that higher phosphate levels associated with a higher risk of presenting atheromatous plaque. This risk however was different according to sex. In men, phosphate levels within the normal range associated with an increased risk of subclinical atheromatosis whereas in women this risk only increased with serum levels over the normal range. CONCLUSIONS: This study demonstrates that phosphate levels are associated with the presence of subclinical atheromatosis in a large CKD population. This effect of phosphate on subclinical atheromatosis was different according to sex, suggesting that a recommended serum phosphate levels could be different for male than for female CKD patients

New perspectives on CKD-induced dyslipidemia

Abstract INTRODUCTION: Chronic kidney disease (CKD) is a world-wide health concern associated with a significantly higher cardiovascular morbidity and mortality. One of the principal cardiovascular risk factors is the lipid profile. CKD patients have a more frequent and progressive atheromatous disease that cannot be explained by the classical lipid parameters used in the daily clinical practice. Areas covered: The current review summarizes prevailing knowledge on the role of lipids in atheromathosis in CKD patients, including an overview of lipoprotein metabolism highlighting the CKD-induced alterations. Moreover, to obtain information beyond traditional lipid parameters, new state-of-the-art technologies such as lipoprotein subfraction profiling and lipidomics are also reviewed. Finally, we analyse the potential of new lipoprotein subclasses as therapeutic targets in CKD. Expert opinion: The CKD-induced lipid profile has specific features distinct from the general population. Besides quantitative alterations, renal patients have a plethora of qualitative lipid alterations that cannot be detected by routine determinations and are responsible for the excess of cardiovascular risk. New parameters, such as lipoprotein particle number and size, together with new biomarkers obtained by lipidomics will personalize the management of these patients. Therefore, nephrologists need to be aware of new insights into lipoprotein metabolism to improve cardiovascular risk assessment.This work was supported by the intramural program of the IRBLleida, Instituto de Salud Carlos III (RETIC RD16/0009/0011, FIS PI16/01354) and FEDER funds

Observational multicenter study to evaluate the prevalence and prognosis of subclinical atheromatosis in a Spanish chronic kidney disease cohort: baseline data from the NEFRONA study

Background: Cardiovascular events (CVE) are more prevalent in chronic kidney disease (CKD) than in general population, being the main cause of morbimortality. Specific risk factors related to CKD have been suggested, because traditional factors do not fully explain this increase in cardiovascular disease rates. However, the role of atheromatosis, its pathogenesis and evolution are still unclear. The potential use of diagnostic tests to detect subclinical atheromatosis has to be determined. Methods: NEFRONA is a prospective multicenter cohort study. 2445 CKD subjects were enrolled from 81 Spanish hospitals and dialysis clinics, from 2010 to 2012. Eligibility criteria included: 18 to 74 years old, CKD stage 3 or higher, and no previous CVE. 559 non-CKD controls were also recruited. Demographical, clinical and analytical data were collected. Carotid and femoral ultrasounds were performed by a single trained team to measure carotid intima-media thickness (cIMT) and detect atheromatous plaques. Ankle-brachial index (ABI) was measured. Results: Differences in age, sex and prevalence and control of cardiovascular risk factors were found between controls and CKD patients. These differences are similar to those described in epidemiological studies. No difference was found regarding cIMT between controls and CKD (when subjects with plaques in common carotid arteries were omitted); earlier CKD stages had higher values. CKD patients had a higher rate of atheromatous plaques, with no difference between stages in the unadjusted analysis. A group of patients had plaques in femoral arteries but were plaque-free in carotid arteries, and would have gone underdiagnosed without the femoral study. The percentage of pathologic ABI was higher in CKD, with higher prevalence in more advanced stages, and a higher rate of ABI >1.4 than <0.9, suggesting more vascular calcification. Conclusions: NEFRONA is the first large study describing the actual prevalence of subclinical atheromatosis across different CKD stages. There is a very high rate of atheromatous plaques and pathologic ABI in CKD. Prospective data will add important information to the pathogenesis and evolution of atheromatosis in CKD, compared to non-CKD subjects

Subclinical Atheromatosis progression and FGF-2 in CKD

Background and objectives: Atherosclerosis is highly prevalent in CKD. The rate of progression of atherosclerosis is associated with cardiovascular events. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family with potentially both protective and deleterious effects in the development of atherosclerosis. The role of circulating FGF-2 levels in the progression of atherosclerosis in CKD is unknown. Design, setting, participants, & measurements: We used a multicenter, prospective, observational cohorts study of 481 patients with CKD. We determined the presence of atheroma plaque in ten arterial territories by carotid and femoral ultrasounds. Progression of atheromatosis was defined as an increase in the number of territories with plaque after 24 months. Plasma levels of FGF-2 were measured by multiplex analysis. A multivariable logistic regression analysis was performed to determine whether plasma FGF-2 levels were associated with atheromatosis progression. Results: Average age of the population was 61 years. The percentage of patients in each CKD stage was 51% in stage 3, 41% in stages 4–5, and 8% in dialysis. A total of 335 patients (70%) showed plaque at baseline. Atheromatosis progressed in 289 patients (67%). FGF-2 levels were similar between patients with or without plaque at baseline (79 versus 88 pg/ml), but lower in patients with atheromatosis progression after 2 years (78 versus 98 pg/ml; P<0.01). In adjusted analyses, higher plasma FGF-2 was associated with lower risk of atheromatosis progression (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.76 to 0.96; per 50 pg/ml increment). Analysis of FGF-2 in tertiles showed that atheroma progression was observed for 102 participants in the lowest tertile of FGF-2 (reference group), 86 participants in the middle tertile of FGF-2 (adjusted OR, 0.70; 95% CI, 0.40 to 1.20), and 74 participants in the lowest tertile of FGF-2 (adjusted OR, 0.48; 95% CI, 0.28 to 0.82). Conclusions: Low FGF-2 levels are independently associated with atheromatosis progression in CKD.This work was supported by the intramural program of the IRBLleida, the Instituto de Salud Carlos III (RETIC RD16/0009/0011, FIS PI16/01354) and FEDER funds. The authors would like to thank the NEFRONA team (Eva Castro, Virtudes María, Teresa Molí, Teresa Vidal, Meritxell Soria) and the Biobank of RedInRen for their invaluable support. The NEFRONA study investigator group is listed in the supplementary material

Predictors of subclinical atheromatosis progression in patients at diferent stages of chronic kidney disease after two years of follow-up. The Nefrona study

Background and objectives Ultrasonographic detection of subclinical atheromatosis is a noninvasive method predicting cardiovascular events. Risk factors predicting atheromatosis progression in CKD are unknown. Predictors of atheromatosis progression were evaluated in patients with CKD. Design, setting, participants, & measurements Our multicenter, prospective, observational study included 1553 patients with CKD (2009-2011). Carotid and femoral ultrasounds were performed at baseline and after 24 months. A subgroup of 476 patients with CKD was also randomized to undergo ultrasound examination at 12 months. Progression of atheromatosis was defined as an increase in the number of plaque territories analyzed by multivariate logistic regression. Results Prevalence of atheromatosis was 68.7% and progressed in 59.8% of patients after 24 months. CKD progression was associated with atheromatosis progression, suggesting a close association between pathologies. Variables significantly predicting atheromatosis progression, independent from CKD stages, were diabetes and two interactions of age with ferritin and plaque at baseline. Given that multiple interactions were found between CKD stage and age, phosphate, smoking, dyslipidemia, body mass index, systolic BP (SBP), carotid intima-n-iedia thickness, plaque at baseline, uric acid, cholesterol, 25-hydroxy vitamin D (250H vitamin D), and antiplatelet and phosphate binders use, the analysis was stratified by CKD stages. In stage 3, two interactions (age with phosphate and plaque at baseline) were found, and smoking, diabetes, SBP, low levels of 25OH vitamin D, and no treatment with phosphate binders were positively associated with atheromatosis progression. In stages 4 and 5, three interactions (age with ferritin and plaque and plaque with smoking) were found, and SBP was positively associated with atheromatosis progression. In dialysis, an interaction between body mass index and 25OH vitamin D was found, and age, dyslipidemia, carotid intima-media thickness, low cholesterol, ferritin, and uric acid were positively associated with atheromatosis progression. Conclusions Atheromatosis progression affects more than one half of patients with CKD, and predictive factors differ depending on CKD stage.The work presented here was funded by a research grant from Abbvie,the Spanish Government, and Fondos Europeos de Desarrollo, European Funds for Regional Development (FEDER) funds Thematic Networks for Collaborative Research (RETIC) grant RD12/0021/0026 and Fund for Sanitary Research (FIS) grant PS10/0094

Factors predicting cardiovascular events in chronic kidney disease patients. Role of subclinical atheromatosis extent assessed by vascular ultrasound

Patients with chronic kidney disease (CKD) have an increased incidence of cardiovascular events (CVE). The contribution of subclinical atheromatosis extent, including femoral arteries, to CVE in CKD patients has not been investigated. In this paper, we examine the prognostic value of subclinical atheromatosis extent, assessed as the number of arterial territories with plaque, in predicting the incidence of major and minor CVE. The NEFRONA is a multicenter, prospective cohorts study that recruited 2445 CKD subjects and 559 controls, free from previous cardiovascular disease, in 81 medical centers across Spain. The presence of atheroma plaque was assessed by arterial ultrasound in ten arterial territories (carotid and femoral). The predictive power of the presence or absence of atheroma plaque in any territory was compared with the quantification of atheroma extent as the number of territories with plaque. During the median follow up of 48 months, 216 CVE were reported. Factors predicting the incidence of CVE in the whole cohort were being male, CKD patient, lower levels of 25(OH) vitamin D, higher levels of cholesterol and the extent of subclinical atheromatosis, yielding a higher concordance (C) index than the presence or absence of plaque. In stratified analysis including specific factors of CKD patients not on dialysis, the variables predicting CVE were the same as in the whole cohort, plus higher levels of potassium. Again, the inclusion of the information about atheromatosis as number of territories with plaque, presented a higher C index than the presence or absence of plaque. In the dialysis population, significant variables were older age, diabetes, dialysis vintage and higher levels of cholesterol and phosphate. In this case the higher C index was obtained with the information about plaque presence. Subclinical atheromatosis extent, including femoral arteries, influences CVE in CKD and its detection could improve the prediction of cardiovascular events.The NEFRONA study is funded by a research grant from AbbVie and the Spanish government RETIC (RD16/0009/0011), FIS PI16/01354 and FEDER fund