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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 483-490
The relationship between serum homocysteine and highly sensitive C- reactive protein levels in children on regular hemodialysis


1 Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

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Date of Web Publication18-May-2017
 

   Abstract 

Hyperhomocysteinemia has attracted a lot of attention in renal patients, not only because of its close relationship with renal function but also because it has been implicated as an independent cardiovascular risk factor in these patients. An increased level of C-reactive protein (CRP) has been reported to be a strong predictor of cardiovascular mortality in hemodialysis (HD) patients. The aim of this study was to assess the association between homocysteine (Hcy) and highly sensitive CRP (hsCRP) in cardiovascular risk prediction in children with chronic kidney disease (CKD) on HD. This case-control study was conducted on 40 children with CKD on regular HD and 20 age- and sex-matched healthy children as controls. Their ages ranged from 4 to 18 years, and they were selected from the pediatric nephrology and HD unit at Al-Azhar University Hospital, during the period from May 2015 to April 2016. Complete blood count, serum ferritin, cholesterol, triglycerides, calcium, phosphorus, parathormone (PTH), Hcy, and hsCRP levels were measured in both groups. Measurements of anthropometry and blood pressure (BP) were performed. There was a significant increase in serum Hcy levels in cases than controls; it was 17.22 ± 9.66 pmol/L and 6.32 ± 1.47 pmol/L, respectively (P <0.01). Furthermore, there was a significant increase in hsCRP in patients than controls; 2.73 ± 2.65 and 0.9 ± 0.85, respectively (P <0.01). There was a significant positive correlation between hsCRP and Hcy with BP, cholesterol, triglyceride, PTH, and ferritin levels. Our data highlighted the important correlation between serum Hcy and hsCRP to detect high-risk patients for subsequent cardiovascular disease and utility of preventive strategies that attenuate inflammatory risk.

How to cite this article:
Abdel-Salam M, Ibrahim S, Pessar SA, Al-morsy E. The relationship between serum homocysteine and highly sensitive C- reactive protein levels in children on regular hemodialysis. Saudi J Kidney Dis Transpl 2017;28:483-90

How to cite this URL:
Abdel-Salam M, Ibrahim S, Pessar SA, Al-morsy E. The relationship between serum homocysteine and highly sensitive C- reactive protein levels in children on regular hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2017 Sep 24];28:483-90. Available from: http://www.sjkdt.org/text.asp?2017/28/3/483/206442

   Introduction Top


The number of patients with chronic kidney disease (CKD) who progress to end-stage renal disease (ESRD) has increased. In addi tion to potential progression to ESRD, CKD is also a risk factor for cardiovascular disease (CVD) and death. It is, therefore, a growing problem worldwide.[1]

Homocysteine (Hcy) is thrombogenic, as it increases thromboxane formation, antagonizes nitric oxide, enhances platelet aggregation, and inhibits protein C and thrombomodulin. Hcy is also a potent mitogen for vascular smooth muscle cells.[2],[3] Hyperhomocysteinemia is a frequent condition among patients with ESRD on dialysis and may represent an additional risk factor for increased CVD.[4] Some studies suggest that inflammatory conditions including elevated Hcy are associated with increased arterial stiffness.[5],[6]

It has been hypothesized that inflammatory markers such as highly sensitive C-reactive protein (hsCRP) may provide an adjunctive method for global assessment of cardiovas cular risk.[7],[8],[9] Several large-scale prospective epidemiological studies have shown that plasma levels of hsCRP are strong indepen dent predictors of risk of future myocardial infarction, stroke, peripheral arterial disease, and vascular death among individuals without known CVD.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19]

This study was conducted to assess the Hcy and hsCRP levels in children on regular hemodialysis (HD) and detect their association along with other risk factors for subsequent cardiovascular risk.


   Subjects and Methods Top


We enrolled 40 children with CKD on regular HD during the period from May 2015 to April 2016. The study also included 20 healthy age- and sex-matched children as controls. They were selected from the out patient clinic and HD unit of the Al-Azhar University Hospital. The patient group was on regular HD for longer than three months at the time of the study, for 4 h/setting, three times weekly, using low-flux polysulfone dialyzer and 4008 Fresenius machine. Informed consent was obtained from the parents of the parti cipating children in adherence with the guide lines of the Ethical Committee of Al-Azhar Hospital, Al-Azhar University, Cairo, Egypt. Patients with acute or recent infection, trauma, primary Hcy disorders, and other chronic illness were excluded from the study.

Sample collection

Blood samples were drawn in the morning after an overnight fast of at least 12 h before the start of the mid-week HD session. Venous blood samples (5 mL) were withdrawn and divided into two specimens:

The first specimen (1 mL) was put in ethylenediaminetetraacetic acid tubes for complete blood picture. The second (4 mL) was put in a plain tube and left to clot and then divided into three portions: one portion was sent for bio-chemical study to be performed on the same day; the second portion was stored frozen at -20°C after careful labeling till the time of assay of hsCRP, serum ferritin, and parathormone (PTH); and the third portion of the serum sample was tested for Hcy on the same day.

Homocysteine assay

Serum Hcy was determined by the ARCHITECT Hcy assay, which is a chemilu- minescent microparticle immunoassay for the quantitative determination of total L-Hcy in human serum or plasma on the ARCHITECT System. Hcy values can assist in the diagnosis and treatment of patients suspected of having hyperhomocysteinemia and homocystinuria (ARCHITECT Homocysteine Reagent Kit, Abbott Diagnostics, Wiesbaden, Germany).

To minimize increases in Hcy concentration from synthesis by red blood cells, serum spe cimens obtained after fasting were placed on ice for 10–12 h after collection and before processing.[20] Total concentration of Hcy in plasma of healthy humans (fasting) is low and its level is between 5.0 and 12.0 pmol/L when immunoassay methods are used. When the level is between 16 and 30 pmol/L, it is classi fied as moderate, 31–100 μmol/L is considered intermediate, and a value above 100 pmol/L is classified as severe hyperhomocysteinemia.[21]


   Statistical Analysis Top


Data were collected, revised, coded, and entered to the Statistical Package for the Social Sciences version 20 (SPSS Inc., Chicago, IL, USA). Pearson correlation coefficients were used to assess the relation between two studied parameters in the same group. Spearman’s correlation coefficients were used to assess the relation between two studied parameters in the same group. Receiver operating characteristic curve was used to assess the best cutoff point with sensitivity and specificity.

P value was considered statistically signi ficant as the following: P >0.05: non signi ficant, P <0.05: significant, and P <0.001: highly significant.


   Results Top


[Table 1] shows the comparison between dialysis group and healthy controls regarding anthropometric measurements, demographic data, and blood pressure (BP). There was a significant decrease in patients’ weight and body mass index (BMI) calculated by Z-score, whereas there was a significant increase in both systolic and diastolic BP in dialysis patients compared to the control group.
Table 1: Comparison between the patient group and the controls regarding demographic data, anthropometric measures, and blood pressure.

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[Table 2] shows the comparison between dia lysis children and healthy controls regarding laboratory data, which revealed significant increase in blood urea nitrogen (BUN), crea- tinine, cholesterol, triglyceride, pH, PTH, ferritin, Hcy, and hsCRP serum levels in the patient group than healthy controls, whereas there was a significant decrease in hemoglobin (Hb) and serum calcium (Ca) levels in dialysis children than healthy controls.
Table 2: Comparison between the patient group and the controls regarding laboratory data and homocysteine level.

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[Table 3] shows a correlation between hsCRP and the laboratory data; it revealed a signi ficant positive correlation between hsCRP and BMI, BP (systolic, diastolic), BUN, creatinine, ferritin, Hcy, and PTH, while there was a sig nificant negative correlation between hsCRP and Hb and hematocrit%.
Table 3: Correlation between highly sensitive C-reactive (hsCRP) protein and the clinical and laboratory data in this study.

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[Figure 1] shows a correlation between homo- cysteine and hsCRP. [Figure 2] shows a corre lation between hsCRP and serum cholesterol level. [Figure 3] and [Figure 4] show correlation bet ween hsCRP and BP (systolic and diastolic). Figure 5 shows a correlation between hsCRP and Hb. Figure 6 shows a correlation between hsCRP and PTH.
Figure 1: Correlation between homocysteine and highly sensitive C-reactive protein.

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Figure 2: Correlation between highly sensitive C-reactive protein and cholesterol.

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Figure 3: Correlation between highly sensitive C-reactive protein and systolic blood pressure.

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Figure 4: Correlation between highly sensitive C-reactive protein and diastolic blood pressure.

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[Table 4] shows the cutoff point of Hcy and hsCRP between patients and controls; it revealed that the best cutoff point of Hcy and hsCRP between patients and controls is >9.6 pmol/L and >1.0 mg/L, respectively.
Table 4: Cutoff point of highly sensitive C-reactive protein and homocysteine among cases and controls.

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   Discussion Top


More than a decade ago, CVD was recog nized as a major cause of death in children with advanced CKD. This observation has sparked the publication of multiple studies assessing cardiovascular risk, mechanisms of disease, and early markers of CVD in this population.

Identification of surrogate markers to detect subclinical CVD in CKD children may aid in reducing the global burden of CKD. In the current study, we attempted to assess Hcy and hsCRP levels to evaluate the burden and subsequent cardiovascular risk in children with CKD and to study the relationship between these markers.

We found a significant elevation of Hcy in patients on HD than the control group. Hyper- homocysteinemia is a frequent finding both in adults and children with ESRD.[22],[23],[24] The major route of Hcy clearance from plasma is the kidney, and the rise is due to defective meta bolism of Hcy by the kidney.[21] Hyper- homocysteinemia may lead to an enhancement of the adverse effects of risk factors such as hypertension, smoking, lipid and lipoprotein metabolism, as well as promotion of the development of inflammation.[20] Some studies have suggested that Hcy levels may increase secondary to the occurrence of CVD and/or due to the presence of atherosclerosis.[25]

Current guidelines have not classified Hcy as a CVD risk factor. The analysis by Veeranna et al prospectively validated and showed the incremental value of Hcy levels in predicting adverse CVD beyond the Framingham risk score (FRS). Hcy fulfills the criteria to classify it as a “novel” marker.[26]

It seems unfair to underestimate the utility of Hcy in CVD risk prediction solely because interventions to lower plasma Hcy levels have not shown a favorable outcome regarding the incidence of CVD.[26]

We found significantly higher levels of hsCRP in patients on HD than the control group. The hsCRP level has been shown to be a marker of atherosclerosis in different studies.[25],[26],[27],[28] Accumulating evidence suggests that ESRD is a state of chronic micro- inflammation. Inflammatory mediators such as CRP are closely linked with the prevalence of CVD and survival rates in patients with ESRD.[27]

In the present study, one of the most impor tant findings is a strong association between hsCRP and Hcy. According to the compre hensive literature search, our study is the first which has addressed this issue in children on regular HD. Although an experimental study[28] has suggested that there is a relation between the two, our results are contradictory to obser vations of another study,[29] which reported no association between the increase in Hcy levels and markers of inflammation.

Three large-scale prospective studies have compared directly the relative efficacy of Hcy screening to hsCRP evaluation.[10],[11],[30],[31],[32],[33] In each study, the magnitude of risk prediction asso ciated with hsCRP levels in the top quintile was greater than that associated with similar elevations of Hcy.

A strong correlation was observed between hsCRP and traditional markers of cardio vascular risk including hypertension, dyslipi- demia, anemia, ferritin, and PTH. Hypertension and anemia have been previously reported as risk factors for cardiac disease in pediatric maintenance dialysis patients.[34],[35],[36],[37],[38] The novel risk factors, i.e., hsCRP and Hcy are gaining importance as predictors of vascular events beyond the other traditional markers.

In conclusion, hsCRP and Hcy may provide an adjunctive method for global assessment of cardiovascular risk. We recommend targets for pharmacological intervention or new dialysis modalities to reduce serum hsCRP levels and consequently improve inflammation and cardiovascular risk. More research is needed to validate relationship of hsCRP and Hcy as risk factors for CVD and obtain solid evidence.

 
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Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C- reactive protein levels with mortality in the elderly. Am J Med 1999;106:506-12.  Back to cited text no. 17
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Blacher J, Demuth K, Guerin AP, et al. Association between plasma homocysteine concentrations and cardiac hypertrophy in end- stage renal disease. J Nephrol 1999;12:248-55.  Back to cited text no. 23
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Correspondence Address:
Manal Abdel-Salam
Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo
Egypt
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DOI: 10.4103/1319-2442.206442

PMID: 28540883

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