Correlation of serum phosphate with carotid intimal-medial thickness in children with chronic kidney disease :Farhana Rahman, Jakia Sultana, Mir Shahadat Hossain, Abdullah-Al Mamun, Tahmina Jesmin, Md Habibur Rahman, Ranjit Ranjon Roy, Golam Muin Uddin, Afroza Begum, Paediatric Nephrology Journal of Bangladesh

ORIGINAL ARTICLE
Year : 2022 | Volume : 7 | Issue : 2 | Page : 47--52

Correlation of serum phosphate with carotid intimal-medial thickness in children with chronic kidney disease

Farhana Rahman¹, Jakia Sultana², Mir Shahadat Hossain³, Abdullah-Al Mamun⁴, Tahmina Jesmin⁴, Md Habibur Rahman⁴, Ranjit Ranjon Roy⁴, Golam Muin Uddin⁴, Afroza Begum⁴,
¹ DGHS, Mohakhali, Dhaka, Bangladesh, Bangladesh
² Shahid Ziaur Rahman Medical College and Hospital, Bogura, Bangladesh
³ Sheikh Russel National Gastroliver Institute and Hospital, Dhaka, Bangladesh
⁴ Department of Pediatric Nephrology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Correspondence Address:
Dr. Farhana Rahman
DGHS, Mohakhali, Dhaka
Bangladesh

Abstract

Background: Hyperphosphatemia is a complication of advanced chronic kidney disease (CKD). Increased serum phosphate concentration is a significant risk factor for vascular calcification, which is an advanced form of atherosclerosis. Medial deposition of calcium and phosphorus and the resulting increase in vascular stiffness further contribute to the high prevalence of hypertension. Carotid ultrasound imaging is a useful adjunct for assessment of arterial wall thickness in patients with CKD. Objective: To assess the correlation of serum phosphate with carotid intimal-medial thickness in children with CKD. Materials and Methods: This cross sectional study was carried out in the Department of Pediatric Nephrology and Department of Radiology and Imaging, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, from July 2018 to December 2019. All the CKD patients with stage III-V aged 2–18 years of both sexes attending the Out-patient and Inpatient Department, BSMMU were enrolled in this study. Patients were diagnosed by history, clinical examination and relevant investigations. The glomerular filtration rate (GFR) was calculated from serum creatinine using Revised Schwartz formula. All participants underwent measurement of carotid intimal- medial thickness(CIMT) by using B mode ultrasonography (Philips, Affiniti 30; USA) with 7.5MHz transducer. Results: Total 43 patients were studied (26 male, 17 female). Mean phosphorous level significantly increased with the advancement of disease. As the stage of CKD increases the mean CIMT also increases. There were moderate positive correlation between serum inorganic phosphate and CIMT in stage III CKD (r = 0.500) and stage V(ND) CKD (r = 0.511) and strong positive correlation in stage IV CKD (r = 0.719) and negligible negative correlation in stage V(D) CKD (r = - 0.057). In multiple regression analysis, serum phosphate was significant(β= 0.673, p= <0.0001) and independent risk factor for increased CIMT in addition to other independent risk factors, including serum calcium and serum PTH. Conclusion: Higher serum phosphate level was one of the significant and independent factor associated with increased CIMT in children with advanced stages of CKD.

How to cite this article:
Rahman F, Sultana J, Hossain MS, Mamun AA, Jesmin T, Rahman MH, Roy RR, Uddin GM, Begum A. Correlation of serum phosphate with carotid intimal-medial thickness in children with chronic kidney disease.Paediatr Nephrol J Bangladesh 2022;7:47-52

How to cite this URL:
Rahman F, Sultana J, Hossain MS, Mamun AA, Jesmin T, Rahman MH, Roy RR, Uddin GM, Begum A. Correlation of serum phosphate with carotid intimal-medial thickness in children with chronic kidney disease. Paediatr Nephrol J Bangladesh [serial online] 2022 [cited 2023 Oct 4 ];7:47-52
Available from: http://www.pnjb-online.org/text.asp?2022/7/2/47/361615

Full Text

Introduction

Chronic kidney disease (CKD) is a progressive and mostly irreversible disease, which is associated with several comorbidities and cardiovascular disease is the most common cause of morbidity and mortality in children with CKD.[1] Estimates of cardiovascular mortality rates in children and young adults who developed end-stage renal disease during childhood are 1,000 times greater than the rates in comparatively aged healthy individuals.[2] Progressive renal dysfunction is associated with multiple biochemical and haemodynamic alterations that profoundly affect the cardiovascular system.

A decline in renal function leads to phosphate retention, elevated parathyroid hormone(PTH) levels, and low 1,25-dihydroxy vitamin D levels; however, serum phosphate levels are often maintained within the normal laboratory range until relatively late in the course of CKD.[3] There is strong observational evidence showing that higher fasting serum phosphate levels are associated with a greater risk for cardiovascular disease in patients with CKD as well as in the general population.[4],[5] Thus, in subjects with normal renal function, serum phosphate was positively associated with carotid intimal-medial thickness (CIMT)[6] and even with mortality[7] independently of traditional cardiovascular risk factors.

The main mechanism involved in the pathophysiology of phosphate-induced cardiovascular risk is vascular calcification. However, high phosphate levels have been also associated with endothelial dysfunction[8] which can increase the risk for atherosclerosis and hypertension.[9]

Structural abnormality on vascular imaging assessed by ultrasound measurement of increased carotid intimal-medial thickness. High prevalence of dyslipidemia[10],[11] and subclinical vascular damage demonstrated by increased CIMT has been reported in children with CKD.[12] Some researcher found that, serum phosphate was strongly correlated with increased CIMT in adult CKD patients.[13],[14] As like as adult patients, hyperphosphatemia may be also an individual risk factor for vascular calcification and cardiovascular morbidity and mortality in pediatric patients. But in this aspect there are limited studies. So this study was designed to assess the correlation of serum phosphate with carotid intimal-medial thickness in children with chronic kidney disease as if effective measures can be taken to prevent hyperphosphatemia induced morbidity.

Materials and Methods

A cross sectional study was done in the Department of Pediatric Nephrology and Department of Radiology and Imaging, BSMMU, Dhaka from July, 2018 to December, 2019. Patients with stage III-V CKD, aged 2 to 18 years of both sexes irrespective of primary cause of CKD, newly diagnosed or previously diagnosed admitted in Inpatient department or attending in the Out-patient department, BSMMU were included in this study. Patients having any congenital heart disease and known family history of dyslipidemia were excluded from the study.

CKD was diagnosed based on history, physical examination, some laboratory investigations like s. creatinine, s. electrolytes, s. calcium, s. inorganic PO4, and intact parathyroid hormone (iPTH). Dietary history regarding phosphate containing diet was taken from previous 3 days dietary recall. eGFR was calculated by revised Schwartz formula as follows-

eGFR= 0.413 x (Height/S. creatinine), here height is expressed in centimetre and serum creatinine in mg/dl[

15]

After measurement of eGFR, each patient was categorised into different stages of CKD.

Blood pressure was measured in a standard fashion by using an aneroid sphygmomanometer by palpatory and auscultatory method. Appropriately sized cuffs were used. Three measurements were taken at 15 minutes intervals in the patient’s right arm in comfortable position and the average of three readings were recorded as the patient’s blood pressure. Then recorded blood pressure was plotted on BP chart (according to age, sex and height) of the Center Disease Control (CDC) growth chart. Body mass index was calculated using the following formula: BMI = Weight (kg) / Height (m)².

Blood was drawn after 8 hour of overnight fasting to measure serum parameters such as creatinine, urea, calcium, inorganic phosphate, parathyroid hormone, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride. From patients on maintainence hemodialysis, blood was collected just before starting hemodialysis session. Measurements were performed using routine laboratory methods.

Measurements of carotid artery intimal-medial thickness

Carotid intimal medial thickness was measured by using B mode ultrasonography (Philips, Affiniti 30; USA) with 7.5MHz transducer. The patients remained on a stretcher in the supine position, neck extended and head turned 45* away from the side being scanned. Intimal- Medial Thickness is defined as distance between the leading edge of first echogenic line (Lumen–Intima interface) and second echogenic line (Media– Adventitia interface) of far wall. Three measurements were taken 0.5, 1 and 2 cm below carotid bifurcation of common carotid artery on each side. The arithmetical averages of these was taken. The IMT of both sides (right and left) was calculated and averages of these two values was used for statistical analysis. Carotid intimal- medial thickness was considered as significant if the thickness was >0.5 mm.[16] For different parameters, mean and standard deviation was calculated. The values of P which was (< 0.05) treated as significant. Carotid intimal-medial thickness (CIMT) measurement was performed by one experienced radiologist blinded to the patients identity and to the study group. This was done in the Department of Radiology and Imaging, BSMMU.

Statistical analysis

Statistical analysis were performed using the software SPSS version 22. For all statistical tests P < 0.05 was considered as statistically significant. Data on the continuous variables were presented as Mean ± SD. Continuous variables were compared through ANOVA test. Pearson correlation test was done to assess the relationship between CIMT and serum phosphate and other clinical variables. Multiple linear regression analysis was used to analyze the effect of several parameters on CIMT.

Results

In this study, out of 43 patients, 6 patients (14%) were in stage III, 9 patients (20.9%) were in stage IV, 16 patients (37.2%) were in stage V(ND) and 12 patients (27.9%) were in stage V(D) [Figure 1]. Among them 26 were male and 17 were female [Table 1]. Causes of CKD include hypoplastic kidney (34.8%), glomerulonephritis (30.2%), obstructive uropathy (20.9%), and others (13.9%). Other causes were polycystic kidney disease, nephrocalcinosis, recurrent UTI, neurogenic bladder.{Figure 1} {Table 1}

Regarding lab parameters serum creatinine, blood urea, eGFR, serum inorganic phosphate and serum PTH were statistically significant (P < 0.001) among study subjects [Table 2].{Table 2}

As the stage of CKD increases the mCIMT increases. In our study mCIMT in Stage III was 0.43 ± 0.04 mm and that of Stage IV, Stage V(ND) and VD were 0.53 ± 0.05 mm, 0.67 ± 0.07 mm and 0.60 ± 0.07 mm respectively [Table 3].{Table 3}

Pearson correlation test was done to assess the relationship between CIMT and clinical parameters [Table 4]. There was a high positive correlation between serum inorganic phosphate, calcium-phosphate product with CIMT (correlation coefficient r = 0.715 and 0.742 respectively); moderate positive correlation between serum PTH with CIMT (correlation coefficient r = 0.660) and low positive correlation between diastolic blood pressure with CIMT (correlation coefficient r = 0.337). However, no significant correlation could be established with systolic blood pressure, total cholesterol, HDL, LDL and triglyceride.{Table 4}

The relationship between CIMT and serum phosphate level in different stages of CKD is shown in [Figure 2]. There was a high positive correlation between serum phosphate and CIMT in stage IV CKD (correlation coefficient r = 0.719); moderate positive correlation in stage III and stage V(ND) CKD (correlation coefficient r = 0.500 and 0.511 respectively) and negligible negative correlation in stage V(D) CKD (correlation coefficient r = - 0.057).{Figure 2}

To examine the combined effect of factors affecting CIMT, multiple linear regression analysis was performed [Table 5]. Here serum inorganic phosphate was signifificant (P = 0.001) independent factor for increased CIMT. Other factors such as serum calcium (P = 0.012) and PTH (P = 0.009) also have effect on CIMT.{Table 5}

Discussion

This study was carried out in 43 children aged 2 to 18 years with CKD. Among them 26 were male (60.5%) and 17 were female (39.5%). One noticeble point of the present study is that more than half (65%) of the enrolled children belongs to stage V CKD. As this is a tertiary care hospital, so most of the patients presented with us with advanced stage of CKD.

In the present study, the mean phosphorous level significantly increased with the advancement of disease [Table 2] which is similar to what was reported in other study.[17] Inorganic phosphate level was significantly higher in stage V(ND) in comparison to stage III, IV and V(D) CKD. The possible cause of comparatably lower serum inorganic phosphate level in stage V(D) CKD was regular dialysis. Hyperphosphatemia is a significant risk factor for vascular complication and reduction of phosphate level by using phosphate binders has been reported to attenuate vascular calcification.[18]

In CKD patients, hyperphosphatemia has been found as a significant risk factor for the development of secondary hyperparathyroidism and uremic bone disease.[19] The present study showed a significant increase in parathyroid hormone level in CKD patients with advancement of disease [Table 2]. There are some studies where parathyroid hormone level also increased significantly in predialysis and dialysis group compared with controls.[20],[21]

Dyslipidemia is a common complication of progressive kidney disease, and also an independent risk factor of cardiovascular disease, which is characterized by high level of triglyceride, total cholesterol and low high density lipoprotein (HDL) cholesterol level. In some studies, patients had significant hypertriglyceridemia, increased LDL and low HDL level and these were significantly associated with increased CIMT.[12],[22] In present study we found no significant association between lipid profile and CIMT [Table 4].

CIMT, has been reported to be an early marker of atherosclerosis and predictor of vascular events, that can be measured by noninvasive ultrasonography. In the present study mean CIMT was raised as the disease progresses [Table 3]. This is consistent with the findings of other studies.[17],[23],[24]

In this study, there were moderate positive correlation between serum inorganic phosphate and intimal- medial thickness in stage III CKD (r = 0.500) and stageV(ND) CKD (r = 0.511) and strong positive correlation in stage IV CKD (r = 0.719) [Figure 2]. Whereas there was negligible negative correlation between serum inorganic phosphate and intimal- medial thickness in stage VD CKD(r = - 0.057). This agrees with the result of other studies.[17],[25] Inorganic phosphate has been reported to induce phenotypic change of vascular smooth muscle cells into osteoblast- like cells[26],[27] and also induced by core-binding factor a 1, a key transcription factor in osteoblastic differentiation, in vascular smooth cells. These findings suggest that hyperphosphatemia may induce osteoblastic phenotypic changes in vascular smooth muscle cells and vascular cell proliferation that leads to increased arterial wall thickness in patients with CKD.

Hypertension is another most common complication of CKD. There was significant positive correlation between CIMT and systolic and diastolic blood pressure found in several studies.[12],[21] But in present study, there was no significant association found between blood pressure with CIMT [Table 4]. This may be due to the fact that majority of the study subjects were on antihypertensive therapy.

The present study revealed that serum phosphate was significant (β = 0.673, p= <0.0001) and independent risk factors for increased CIMT in addition to other independent risk factors, including raised serum calcium and raised serum PTH [Table 5]. This is consistent with the findings of other studies.[13],[14] Serum phosphate level may be an indicator of increasedCIMT, so it should be screened and monitored routinely in children with CKD.

The present study had some limitations. First, the sample size was relatively small and second, It was a single centre study. Therefore, multicentric studies with larger sample size may be needed to corroborate these findings.

Conclusion

Higher serum phosphate level was one of the significant and independent factor associated with increased CIMT in children with advanced stages of CKD. Optimal control of hyperphosphatemia by appropriate intervention is crucial to prevent future morbidities and mortalities in CKD patients.

Acknowledgement

All authors would like to acknowledge the participants for participation in this work.

Financial support and sponsorship

Nil.

Conflict of interest

None declared.

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