Cardiovascular Disease Risk in Children With Chronic Kidney Disease: Impact of Apolipoprotein C-II and Apolipoprotein C-III

Abstract

Cardiovascular disease (CVD) is an evolving process that begins in the early stages of chronic kidney disease (CKD) in children. Several surrogate markers, such as ambulatory blood pressure monitoring (ABPM), left ventricular (LV) mass, and arterial stiffness assessment, allow for the early detection of subclinical CVD in pediatric CKD. Four groups of plasma samples (n = 3/group) from congenital anomalies of the kidney and urinary tract (CAKUT), as well as non-CAKUT patients with or without BP abnormalities, were studied to screen differentially expressed proteins using isobaric tags for relative and absolute protein quantification (iTRAQ)-based proteomics. As a result, 20 differentially expressed proteins associated with hypertension in children with CKD were discovered. Among them, apolipoprotein C-II (apoC-II) was found to have the highest abundance among the CKD patients with hypertension. As such, we hypothesized that apoC-II and apolipoprotein C-III (apoC-III) levels were related to BP abnormalities and CVD in children suffering from mild-to-moderate CKD. We examined their associations with surrogate markers of CV risk in 88 pediatric patients with CKD stages G1–G4. Children with CKD stages G2–G4 had a higher plasma apoC-II level than G1 patients (6.35 vs. 5.05 mg/dl, p < 0.05). We observed that ABPM abnormalities, LV mass, and arterial stiffness parameters were greater in CKD children who had stages G2–G4 than in those who had stage G1 (all p < 0.05). Plasma levels of apoC-II and apoC-III were positively correlated with total cholesterol, triglyceride, and low-density lipoprotein (LDL) (all p < 0.001). In multivariate linear regression analyses, apoC-II was correlated with a high LV mass index and an abnormal ABPM profile, and apoC-III was correlated with 24-h hypertension (r = 0.303, p = 0.003) and asleep hypertension (r = 0.379, p < 0.001). Early evaluations of apoC-II and apoC-III, ABPM, and surrogate markers of CV risk will aid in early preventative interventions to reduce the risk of CV in youths suffering from CKD.

Pregnancy Zone Protein as an Emerging Biomarker for Cardiovascular Risk in Pediatric Chronic Kidney Disease

“…This is in line with prior work revealing that certain CVD risk markers already appear in children with early stages of CKD, for example, abnormalities in ABPM [ 6 , 8 , 10 , 11 , 16 ]. Although the severity of CKD was reported to be associated with high PWV and LV mass [ 8 ], we observed that these CV markers were not different between the two groups classified by the presence or absence of CAKUT.…”

“…Currently, proteomics research has been broadly employed to identify protein biomarkers in many diseases [ 15 ]. Our previous study using a proteomic approach identified 20 differentially expressed proteins between CKD children with CAKUT or non-CAKUT and with or without ABPM abnormalities [ 16 ]. Our findings identified pregnancy zone protein (PZP), which will be validated in the current study to elucidate its association with CV risk in CKD children.…”

Cardiovascular Risks of Hypertension: Lessons from Children with Chronic Kidney Disease

“…Among them, children with CKD stages 2–4 had a higher plasma apolipoprotein II (ApoC-II) level than those with CKD stage 1. Additionally, ApoC-II was correlated with LVH and an abnormal ABPM profile [ 114 ]. In a consequent study, another proteomic biomarker complement factor H (CFH) and related proteins were studied in 102 children with CKD stages 1–4 [ 115 ].…”

Complement Factor H and Related Proteins as Markers of Cardiovascular Risk in Pediatric Chronic Kidney Disease

“…Combined with mass spectrometry, isobaric tags for relative and absolute protein quantification (iTRAQ) have been valuable in discovering potential protein biomarkers [ 8 ]. Our previous study using the iTRAQ technique identified several potential proteins expressed differentially between children with CKD with or without ABPM abnormalities, including complement factor H (CFH), CFH-related protein-2 (CFHR2), and CFH-related protein-3 (CFHR3) [ 9 ].…”

“…The CFHR proteins can be divided into two groups according to dimerization or not, as circulating in plasma: CFHR2 existing in dimeric form belongs to group 1, while group 2, including CFHR3, is oligomeric [ 12 ]. Considering the competition between CFHRs and CFH for binding to C3b, as described in [ 9 ], we assumed that simultaneous analysis of CFH, CFHR2, and CFHR3 might provide more information to reflect the homeostasis of the complement system.…”