Original article
Is serum Osteopontin a predictor of carotid atherosclerosis severity among prevalent hemodialysis patients?¿Es la osteopontina sérica un factor predictivo de la gravedad de la aterosclerosis carotídea en los pacientes prevalentes en hemodiálisis?

https://doi.org/10.1016/j.arteri.2021.11.004Get rights and content

Abstract

Background and aim

Chronic hemodialysis (HD) patients are among the highest population risk for accelerated atherosclerosis. Osteopontin (OPN) is a multifunctional protein that is increased in chronic kidney disease that may play a role in vascular remodelling and intimal proliferation.

Aim

To assess the relation between OPN levels and severity of carotid atherosclerosis among prevalent HD patients.

Methods

Eighty chronic HD patients underwent serum OPN levels assessment and were further classified into 3 subgroups according to the OPN tertiles’ levels; sub-group 1 (lower tertile) subgroup 2 (middle tertile) and sub-group 3 (upper tertile), together with the carotid duplex and Transthoracic Doppler Echocardiography examination.

Results

The mean carotid intima-media thickness (CIMT) was 0.89 ± 0.14 mm. Out of the studied group, 50 (62.5%) patients had atheromatous plaques and 15 patients (18.8%). had significant stenosis. The 3rd group with the upper OPN tertile (78–270 ng/dl) had the highest incidence of atherosclerosis. A significant correlation between the OPN levels and the CIMT (r = 0.533, p = 0.001). OPN values detect atherosclerosis with diagnostic sensitivity of 70%, specificity of 69%, positive predictive value (PPV) 73%, negative predictive value (NPV) 65% with area under the curve (AUC) 0.804 (95% CI: 0.711–0.897). Serum OPN detect carotid stenosis with sensitivity of 66%, specificity of 81%, PPV 45%, NPV 91% with AUC = 0.769 and detect the presence of carotid atheroma with sensitivity 70%, specificity 66.67%, PPV 77.8%, NPV 57.1% and AUC = 0.767 (p-value < 0.001). Moreover, serum levels of OPN were significantly positively correlated with grade of diastolic dysfunction (r = 0.312, p = 0.005), E/A ratio (r = 0.293, p = 0.008) and inversely correlated with left ventricular ejection fraction (r = −0.304, p = 0.006).

Conclusions

Serum Osteopontin is of clinical value as a predictor biomarker of the severity of carotid atherosclerosis, presence of atheroma and carotid stenosis with high diagnostic sensitivity and specificity in chronic hemodialysis patients. Increased Osteopontin level is associated with left ventricular diastolic and systolic dysfunction in those patients.

Resumen

Antecedentes y objetivo

Los pacientes de hemodiálisis crónica (HD) son una de las poblaciones de mayor riesgo de aterosclerosis acelerada. La osteopontina (OPN) es una proteína multifuncional que se incrementa en la enfermedad renal crónica, y que puede jugar un papel en la remodelación vascular y la proliferación de la íntima.

Objetivo

Evaluar la relación entre los niveles de OPN y la gravedad de la aterosclerosis carotídea en los pacientes prevalentes en HD.

Métodos

Se evaluó el nivel sérico de OPN en 80 pacientes de HD crónica. Seguidamente, se clasificó a dichos pacientes en tres subgrupos con arreglo a los niveles de los terciles de OPN: subgrupo 1 (tercil inferior) subgrupo 2 (tercil medio) y subgrupo 3 (tercil superior), junto con dúplex carotídeo y ecocardiografía Doppler transtorácica.

Resultados

El espesor medio de la íntima-media carotídea (CIMT) fue de 0,89 ± 0,14 mm. En el grupo estudiado, 50 (62,5%) pacientes tenían placas ateromatosas y 15 pacientes (18,8%) tenían estenosis significativa. El tercer grupo, con tercil OPN (78-270 ng/dL) reflejó la mayor incidencia de aterosclerosis. Existió una correlación significativa entre los niveles de OPN y CIMT (r = 0,533, p = 0,001). Los valores de OPN detectaron aterosclerosis con una sensibilidad diagnóstica del 70%, especificidad del 69%, valor predictivo positivo (VPP) del 73%, valor predictivo negativo (VPN) del 65% y área bajo la curva (AUC) de 0,804 (intervalo de confianza [IC] 95%: 0,711-0,897). La OPN detectó estenosis carotídea con una sensibilidad del 66%, especificidad del 81%, VPP del 45%, VPN del 91%, y AUC = 0,769 y detectó la presencia de ateroma carotídeo con una sensibilidad del 70%, especificidad del 66,67%, VPP del 77,8%, VPN del 57,1% y AUC = 0,767 (valor p < 0,001). Además, los niveles séricos de OPN se correlacionaron positiva y significativamente con el grado de disfunción diastólica (r = 0,312, p = 0,005), ratio E/A (r = 0,293, p = 0,008) y guardaron una correlación inversa con la fracción de eyección ventricular izquierda (r = -0,304, p = 0,006).

Conclusiones

La osteopontina sérica tiene valor clínico como biomarcador predictivo de la severidad de la aterosclerosis carotídea, presencia de ateroma y estenosis carotídea con alta sensibilidad y especificidad diagnóstica en los pacientes de hemodiálisis crónica. Además, la OPN puede jugar un papel en el desarrollo de la disfunción diastólica ventricular izquierda y la disfunción sistólica en estos pacientes.

Introduction

The prevalence of cardiovascular diseases (CVD) is about 70% among hemodialysis patients as reported by USRDS Annual Data Reports, CVD is a major cause of mortality among ESRD patients.1 The NEFRONA study confirmed an increased prevalence of atherosclerosis in chronic kidney disease (CKD) patients.2 Several factors in end-stage renal disease (ESRD) patients may contribute to atherosclerosis and arterial stiffness risk, for instance, inflammations, over-activity of the rennin-angiotensin system, volume overload, and CKD–mineral and bone disorder such as increased calcium-phosphate product and vascular calcification.3

Osteopontin (OPN) is a secreted multifunctional glycol-phospho-protein found widely in bone, kidney, and other tissues.4 Elevated serum levels are highly expressed in several pathologies with a chronic inflammatory component including CKD.5 OPN has been classified as a T-helper 1 cytokine and so believed to exacerbate inflammation including atherosclerosis.6 OPN is a highly negatively charged, extracellular matrix protein, It is composed of about 314 amino acids in humans and is expressed as a 33-kDa and molecular weight may be increased to about 44 kDa as OPN can go through posttranslational modifications,7 so OPN is non-dialyzable protein. Moreover, serum OPN levels were noted significantly higher in hemodialysis (HD) groups than CKD patients pre-HD, and healthy volunteer groups which may be attributed to uraemia and the dialysis procedure itself.8

Despite the careful monitoring of CKD patients, there is an increased risk of cardiovascular diseases.9 Traditional risk factors for atherosclerosis include age, smoking, hypertension, diabetes, and dyslipidemia.10 Many new risk factors for atherosclerosis have emerged over the past years including OPN.

OPN serum levels in patients with cardiovascular disease are assumed to reflect the extent of atherosclerosis and may play a role in plaque formation and vascular disease progression. The objective of this study was to assess OPN levels and their correlation to the progression of atherosclerosis in patients with ESRD.

Section snippets

Study population

This is a cross-sectional study that included clinically stable ESRD adult patients undergoing regular HD > 6 months, 3 sessions per week, 4 h per session by bicarbonate dialysate, low flux dialyzer and heparin was used as an anticoagulant.

Patients suffering from an active bacterial or viral infection, severe hepatic failure, autoimmune diseases and connective tissue diseases, malignancy, decompensated heart failure, history of surgery and trauma within 1 month, were excluded from the study.

The

Results

Out of 115 patients referred to the hemodialysis unit in the study period, 80 patients were enrolled in the study, 35 patients were excluded due to the presence of heart failure, malignancy and autoimmune diseases. The study included 80 clinically stable ESRD adult patients undergoing regular hemodialysis > 6 months. The mean age of the study population was 54.60 ± 11.02 years. The duration of hemodialysis was 5.95 ± 4.72 years, the demographic characteristics of the studied group are presented in

Discussion

OPN was first described in 1985 by Franzen and Heinegard as a type of sialoproteins derived from the bovine bone matrix.19 It is a secreted adhesive molecule that functions in part as an inflammatory cytokine; it is thought to aid in the recruitment of monocytes-macrophages and regulate cytokine production in macrophages, dendritic cells and T-cells.6 OPN plays a role in the migration of endothelial cells, proliferation, and/or differentiation of vascular smooth muscle cells along with plaque

Conclusion

Serum Osteopontin is of clinical value as a predictor biomarker of the severity of carotid atherosclerosis, presence of atheroma and carotid stenosis with high diagnostic sensitivity and specificity in chronic hemodialysis patients. Increased Osteopontin level is associated with left ventricular diastolic and systolic dysfunction in those patients.

Limitations

Cross-sectional study and a small number of patients as no fund was received.

Authors’ contribution

Maha A. Behairy: Conceptualization; Formal analysis; Investigation; Methodology; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.

Sahar Mahmoud Shawky: Supervision.

Reham Abd Elaziz Hamed: Data curation; Formal analysis; Investigation.

Somia Abd El Hamid Bawady: Data curation; Formal analysis; Investigation; Methodology; Supervision; Writing – original draft; Writing – review & editing.

Hoda A. Abdelsattar: Data curation; Investigation; Methodology;

Ethics approval

All procedures performed in the study were following ethical standards of the Ain-Shams University hospital research committee (Ethics committee reference number 000017585) and with the ethical standards laid down in the 1964 Declaration of Helsinki.

Consent to participate

An informed written consent was obtained from all patients enrolled in the study.

Consent for publication

All copyright ownership for the article is transferred to the journal upon acceptance.

Funding/support

No source of funding was obtained to support the study.

Conflicts of interest

No conflict of interest.

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